Skip to main content
SpringerLink
Log in

Targeting Epigenetic Regulators in Cancer to Overcome Resistance to Targeted Therapy

  • Chapter
  • First Online:
Current Applications for Overcoming Resistance to Targeted Therapies

Part of the book series: Resistance to Targeted Anti-Cancer Therapeutics ((RTACT,volume 20))

Abstract

Resistance to cancer therapy is an ongoing challenge, and there is a need to seek out non-traditional approaches such as targeting epigenetic components for cancer therapy. Epigenomics provides essential tools not only for therapeutic intervention but also as predictors of drug response. Unlike alteration of genetic components, where the structure of a gene is changed, such as mutations, deletions, additions, and single nucleotide polymorphisms, epigenetics changes gene expression without altering the genetic sequence. Furthermore, several epigenetic changes are reversible, and as a result, drugs have been developed that can reverse the epigenetic changes associated with different cancers. These epigenetic drugs target DNA methyltransferases, histone deacetylases and proteins associated with post-transcriptionally modified histones. Epigenetic regulators represent potential therapeutic targets as they often have binding domains that lend themselves well to small molecule inhibition. Here, we discuss factors that contribute to the development of resistance to targeted therapy and how epigenetic regulators can be utilized to overcome this resistance. We provide examples of several cancer types for which conventional targeted therapy has limited effects, but improved treatment outcomes are observed following epigenetic reprogramming of gene expression patterns, including modification of histones and DNA. Results from clinical trials have indicated the efficacy of epigenetic drugs as cancer therapy, mainly when administered in combination with traditional anticancer drugs. These promising data suggest that epigenetic drugs have great potential in controlling and treating cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover + eBook
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
  • Available as EPUB and PDF
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

AUC:

Area under curve

CDKN1:

Cyclin-dependent kinase inhibitor 1

CRC:

Colorectal cancer

CRPC:

Castration resistant prostate cancer

CSCs:

Cancer stem cells

DNMTs:

DNA methyltransferases

EMT:

Epithelial-to-mesenchymal transition

EZH2:

Enhancer of zeste homolog 2

HATs:

Histone acetyltransferases

HCC:

Hepatocellular carcinoma

HDAC:

Histone deacetylase

HER2:

Human epidermal growth factor receptor

HY-PDT:

Hypericin-mediated photodynamic therapy

KMTs:

Histone lysine methyltransferases

LINE:

Long interspersed nuclear elements

miRs:

Micro RNAs

NaPB:

3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide

NSCLC:

Non-small cell lung cancer

oncomiR:

Oncogenic miRNAs

ORR:

Overall response rate

PSA:

Prostate-specific antigen

RCC:

Renal cell carcinoma

SAHA:

Suberoylanilide hydroximic acid

SINE:

Short interspersed nuclear elements

TET:

Ten-eleven translocation protein family

TSA:

Trichostatin A

VEGF:

Vascular endothelial growth factor

VPA:

Valproic acid

References

  1. Jones P. Out of Africa and into epigenetics: discovering reprogramming drugs. Nat Cell Biol. 2011;13(1):2. https://doi.org/10.1038/ncb0111-2.

    Article  CAS  PubMed  Google Scholar 

  2. Jones PA. Overview of cancer epigenetics. Semin Hematol. 2005;42(3 Suppl 2):S3–8.

    Article  CAS  PubMed  Google Scholar 

  3. Jones PA, Laird PW. Cancer epigenetics comes of age. Nat Genet. 1999;21(2):163–7. https://doi.org/10.1038/5947.

    Article  CAS  PubMed  Google Scholar 

  4. Jones PA, Takai D. The role of DNA methylation in mammalian epigenetics. Science. 2001;293(5532):1068–70. https://doi.org/10.1126/science.1063852.

    Article  CAS  PubMed  Google Scholar 

  5. Khare S, Verma M. Epigenetics of colon cancer. Methods Mol Biol. 2012;863:177–85. https://doi.org/10.1007/978-1-61779-612-8_10.

    Article  CAS  PubMed  Google Scholar 

  6. Jones PA, Issa JP, Baylin S. Targeting the cancer epigenome for therapy. Nat Rev Genet. 2016;17(10):630–41. https://doi.org/10.1038/nrg.2016.93.

    Article  CAS  PubMed  Google Scholar 

  7. Baylin SB. Tying it all together: epigenetics, genetics, cell cycle, and cancer. Science. 1997;277(5334):1948–9.

    Article  CAS  PubMed  Google Scholar 

  8. Baylin SB. Stem cells, cancer, and epigenetics. Cambridge: StemBook; 2008.

    Google Scholar 

  9. Baylin SB. Resistance, epigenetics and the cancer ecosystem. Nat Med. 2011;17(3):288–9. https://doi.org/10.1038/nm0311-288.

    Article  CAS  PubMed  Google Scholar 

  10. Jones B. Epigenetics: histones pass the message on. Nat Rev Genet. 2015;16(1):3. https://doi.org/10.1038/nrg3876.

    Article  CAS  PubMed  Google Scholar 

  11. Sharma S, Kelly TK, Jones PA. Epigenetics in cancer. Carcinogenesis. 2010;31(1):27–36. https://doi.org/10.1093/carcin/bgp220.

    Article  CAS  PubMed  Google Scholar 

  12. You JS, Jones PA. Cancer genetics and epigenetics: two sides of the same coin? Cancer Cell. 2012;22(1):9–20. https://doi.org/10.1016/j.ccr.2012.06.008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Verma M. Epigenome-Wide Association Studies (EWAS) in cancer. Curr Genomics. 2012;13(4):308–13. https://doi.org/10.2174/138920212800793294.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Mishra A, Verma M. Epigenetics of solid cancer stem cells. Methods Mol Biol. 2012;863:15–31. https://doi.org/10.1007/978-1-61779-612-8_2.

    Article  CAS  PubMed  Google Scholar 

  15. Verma M. Genome-wide association studies and epigenome-wide association studies go together in cancer control. Future Oncol. 2016;12(13):1645–64. https://doi.org/10.2217/fon-2015-0035.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Yu T, Wang C, Yang J, Guo Y, Wu Y, Li X. Metformin inhibits SUV39H1-mediated migration of prostate cancer cells. Oncogene. 2017;6(5):e324. https://doi.org/10.1038/oncsis.2017.28.

    Article  CAS  Google Scholar 

  17. Metzger E, Wissmann M, Yin N, Muller JM, Schneider R, Peters AH, et al. LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature. 2005;437(7057):436–9. https://doi.org/10.1038/nature04020.

    Article  CAS  PubMed  Google Scholar 

  18. Adorno-Cruz V, Kibria G, Liu X, Doherty M, Junk DJ, Guan D, et al. Cancer stem cells: targeting the roots of cancer, seeds of metastasis, and sources of therapy resistance. Cancer Res. 2015;75(6):924–9. https://doi.org/10.1158/0008-5472.CAN-14-3225.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Komura K, Jeong SH, Hinohara K, Qu F, Wang X, Hiraki M, et al. Resistance to docetaxel in prostate cancer is associated with androgen receptor activation and loss of KDM5D expression. Proc Natl Acad Sci U S A. 2016;113(22):6259–64. https://doi.org/10.1073/pnas.1600420113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Plimack ER, Kantarjian HM, Issa JP. Decitabine and its role in the treatment of hematopoietic malignancies. Leuk Lymphoma. 2007;48(8):1472–81. https://doi.org/10.1080/10428190701471981.

    Article  CAS  PubMed  Google Scholar 

  21. Plimack ER, Stewart DJ, Issa JP. Combining epigenetic and cytotoxic therapy in the treatment of solid tumors. J Clin Oncol. 2007;25(29):4519–21. https://doi.org/10.1200/JCO.2007.12.6029.

    Article  CAS  PubMed  Google Scholar 

  22. Verma M, Maruvada P, Srivastava S. Epigenetics and cancer. Crit Rev Clin Lab Sci. 2004;41(5–6):585–607. https://doi.org/10.1080/10408360490516922.

    Article  CAS  PubMed  Google Scholar 

  23. Fan H, Lu X, Wang X, Liu Y, Guo B, Zhang Y, et al. Low-dose decitabine-based chemoimmunotherapy for patients with refractory advanced solid tumors: a phase I/II report. J Immunol Res. 2014;2014:371087. https://doi.org/10.1155/2014/371087.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Nie J, Liu L, Li X, Han W. Decitabine, a new star in epigenetic therapy: the clinical application and biological mechanism in solid tumors. Cancer Lett. 2014;354(1):12–20. https://doi.org/10.1016/j.canlet.2014.08.010.

    Article  CAS  PubMed  Google Scholar 

  25. Toyota M, Ahuja N, Suzuki H, Itoh F, Ohe-Toyota M, Imai K, et al. Aberrant methylation in gastric cancer associated with the CpG island methylator phenotype. Cancer Res. 1999;59(21):5438–42.

    CAS  PubMed  Google Scholar 

  26. Chawla JP, Iyer N, Soodan KS, Sharma A, Khurana SK, Priyadarshni P. Role of miRNA in cancer diagnosis, prognosis, therapy and regulation of its expression by Epstein-Barr virus and human papillomaviruses: with special reference to oral cancer. Oral Oncol. 2015;51(8):731–7. https://doi.org/10.1016/j.oraloncology.2015.05.008.

    Article  CAS  PubMed  Google Scholar 

  27. Gilot D, Galibert MD. miRNA displacement as a promising approach for cancer therapy. Mol Cell Oncol. 2018;5(1):e1406432. https://doi.org/10.1080/23723556.2017.1406432.

    Article  CAS  PubMed  Google Scholar 

  28. Kopcalic K, Petrovic N, Stanojkovic TP, Stankovic V, Bukumiric Z, Roganovic J, et al. Association between miR-21/146a/155 level changes and acute genitourinary radiotoxicity in prostate cancer patients: a pilot study. Pathol Res Pract. 2018;215(4):626–31. https://doi.org/10.1016/j.prp.2018.12.007.

    Article  CAS  PubMed  Google Scholar 

  29. Yin C, Fang C, Weng H, Yuan C, Wang F. Circulating microRNAs as novel biomarkers in the diagnosis of prostate cancer: a systematic review and meta-analysis. Int Urol Nephrol. 2016;48(7):1087–95. https://doi.org/10.1007/s11255-016-1281-4.

    Article  CAS  PubMed  Google Scholar 

  30. Geretto M, Pulliero A, Rosano C, Zhabayeva D, Bersimbaev R, Izzotti A. Resistance to cancer chemotherapeutic drugs is determined by pivotal microRNA regulators. Am J Cancer Res. 2017;7(6):1350–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Ors-Kumoglu G, Gulce-Iz S, Biray-Avci C. Therapeutic microRNAs in human cancer. Cytotechnology. 2019;71(1):411–25. https://doi.org/10.1007/s10616-018-0291-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Li H, Liu J, Chen J, Wang H, Yang L, Chen F, et al. A serum microRNA signature predicts trastuzumab benefit in HER2-positive metastatic breast cancer patients. Nat Commun. 2018;9(1):1614. https://doi.org/10.1038/s41467-018-03537-w.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sannigrahi MK, Sharma R, Singh V, Panda NK, Rattan V, Khullar M. Role of host miRNA Hsa-miR-139-3p in HPV-16-induced carcinomas. Clin Cancer Res. 2017;23(14):3884–95. https://doi.org/10.1158/1078-0432.CCR-16-2936.

    Article  CAS  PubMed  Google Scholar 

  34. Yun MR, Lim SM, Kim SK, Choi HM, Pyo KH, Kim SK, et al. Enhancer remodeling and microRNA alterations are associated with acquired resistance to ALK inhibitors. Cancer Res. 2018;78(12):3350–62. https://doi.org/10.1158/0008-5472.CAN-17-3146.

    Article  CAS  PubMed  Google Scholar 

  35. Zhao F, Pu Y, Cui M, Wang H, Cai S. MiR-20a-5p represses the multi-drug resistance of osteosarcoma by targeting the SDC2 gene. Cancer Cell Int. 2017;17:100. https://doi.org/10.1186/s12935-017-0470-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ma J, Lin Y, Zhan M, Mann DL, Stass SA, Jiang F. Differential miRNA expressions in peripheral blood mononuclear cells for diagnosis of lung cancer. Lab Invest. 2015;95(10):1197–206. https://doi.org/10.1038/labinvest.2015.88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Rachagani S, Macha MA, Menning MS, Dey P, Pai P, Smith LM, et al. Changes in microRNA (miRNA) expression during pancreatic cancer development and progression in a genetically engineered KrasG12D;Pdx1-Cre mouse (KC) model. Oncotarget. 2015;6(37):40295–309. https://doi.org/10.18632/oncotarget.5641.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Donzelli S, Mori F, Biagioni F, Bellissimo T, Pulito C, Muti P, et al. MicroRNAs: short non-coding players in cancer chemoresistance. Mol Cell Ther. 2014;2:16. https://doi.org/10.1186/2052-8426-2-16.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Fabbri M, Bottoni A, Shimizu M, Spizzo R, Nicoloso MS, Rossi S, et al. Association of a microRNA/TP53 feedback circuitry with pathogenesis and outcome of B-cell chronic lymphocytic leukemia. JAMA. 2011;305(1):59–67. https://doi.org/10.1001/jama.2010.1919.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Meng X, Fu R. miR-206 regulates 5-FU resistance by targeting Bcl-2 in colon cancer cells. Onco Targets Ther. 2018;11:1757–65. https://doi.org/10.2147/OTT.S159093.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Todorova K, Metodiev MV, Metodieva G, Mincheff M, Fernandez N, Hayrabedyan S. Micro-RNA-204 participates in TMPRSS2/ERG regulation and androgen receptor reprogramming in prostate cancer. Horm Cancer. 2017;8(1):28–48. https://doi.org/10.1007/s12672-016-0279-9.

    Article  CAS  PubMed  Google Scholar 

  42. Verma M. Cancer epigenetics: risk assessment, diagnosis, treatment, and prognosis. Preface. Methods Mol Biol. 2015;1238:v–vi.

    PubMed  Google Scholar 

  43. Gore L, Triche TJ Jr, Farrar JE, Wai D, Legendre C, Gooden GC, et al. A multicenter, randomized study of decitabine as epigenetic priming with induction chemotherapy in children with AML. Clin Epigenetics. 2017;9:108. https://doi.org/10.1186/s13148-017-0411-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Abaza YM, Kadia TM, Jabbour EJ, Konopleva MY, Borthakur G, Ferrajoli A, et al. Phase 1 dose escalation multicenter trial of pracinostat alone and in combination with azacitidine in patients with advanced hematologic malignancies. Cancer. 2017;123(24):4851–9. https://doi.org/10.1002/cncr.30949.

    Article  CAS  PubMed  Google Scholar 

  45. Diyabalanage HV, Granda ML, Hooker JM. Combination therapy: histone deacetylase inhibitors and platinum-based chemotherapeutics for cancer. Cancer Lett. 2013;329(1):1–8. https://doi.org/10.1016/j.canlet.2012.09.018.

    Article  CAS  PubMed  Google Scholar 

  46. Suraweera A, O’Byrne KJ, Richard DJ. Combination therapy with histone deacetylase inhibitors (HDACi) for the treatment of cancer: achieving the full therapeutic potential of HDACi. Front Oncol. 2018;8:92. https://doi.org/10.3389/fonc.2018.00092.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Li J, Hao D, Wang L, Wang H, Wang Y, Zhao Z, et al. Epigenetic targeting drugs potentiate chemotherapeutic effects in solid tumor therapy. Sci Rep. 2017;7(1):4035. https://doi.org/10.1038/s41598-017-04406-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Baretti M, Azad NS. The role of epigenetic therapies in colorectal cancer. Curr Probl Cancer. 2018;42(6):530–47. https://doi.org/10.1016/j.currproblcancer.2018.03.001.

    Article  PubMed  Google Scholar 

  49. Zain J, Kaminetzky D, O’Connor OA. Emerging role of epigenetic therapies in cutaneous T-cell lymphomas. Expert Rev Hematol. 2010;3(2):187–203. https://doi.org/10.1586/ehm.10.9.

    Article  CAS  PubMed  Google Scholar 

  50. Vera O, Rodriguez-Antolin C, de Castro J, Karreth FA, Sellers TA, Ibanez de Caceres I. An epigenomic approach to identifying differential overlapping and cis-acting lncRNAs in cisplatin-resistant cancer cells. Epigenetics. 2018;13(3):251–63. https://doi.org/10.1080/15592294.2018.1436364.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Panja S, Hayati S, Epsi NJ, Parrott JS, Mitrofanova A. Integrative (epi) genomic analysis to predict response to androgen-deprivation therapy in prostate cancer. EBioMedicine. 2018;31:110–21. https://doi.org/10.1016/j.ebiom.2018.04.007.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Sharma SV, Lee DY, Li B, Quinlan MP, Takahashi F, Maheswaran S, et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell. 2010;141(1):69–80. https://doi.org/10.1016/j.cell.2010.02.027.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Broxterman HJ, Gotink KJ, Verheul HM. Understanding the causes of multidrug resistance in cancer: a comparison of doxorubicin and sunitinib. Drug Resist Updat. 2009;12(4–5):114–26. https://doi.org/10.1016/j.drup.2009.07.001.

    Article  CAS  PubMed  Google Scholar 

  54. Gampenrieder SP, Rinnerthaler G, Hackl H, Pulverer W, Weinhaeusel A, Ilic S, et al. DNA methylation signatures predicting bevacizumab efficacy in metastatic breast cancer. Theranostics. 2018;8(8):2278–88. https://doi.org/10.7150/thno.23544.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Mekala JR, Naushad SM, Ponnusamy L, Arivazhagan G, Sakthiprasad V, Pal-Bhadra M. Epigenetic regulation of miR-200 as the potential strategy for the therapy against triple-negative breast cancer. Gene. 2018;641:248–58. https://doi.org/10.1016/j.gene.2017.10.018.

    Article  CAS  PubMed  Google Scholar 

  56. Jendzelovsky R, Jendzelovska Z, Kucharova B, Fedorocko P. Breast cancer resistance protein is the enemy of hypericin accumulation and toxicity of hypericin-mediated photodynamic therapy. Biomed Pharmacother. 2019;109:2173–81. https://doi.org/10.1016/j.biopha.2018.11.084.

    Article  CAS  PubMed  Google Scholar 

  57. Krammer B, Verwanger T. Molecular response to hypericin-induced photodamage. Curr Med Chem. 2012;19(6):793–8.

    Article  CAS  PubMed  Google Scholar 

  58. Halaburkova A, Jendzelovsky R, Koval J, Herceg Z, Fedorocko P, Ghantous A. Histone deacetylase inhibitors potentiate photodynamic therapy in colon cancer cells marked by chromatin-mediated epigenetic regulation of CDKN1A. Clin Epigenetics. 2017;9:62. https://doi.org/10.1186/s13148-017-0359-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Su Y, Hopfinger NR, Nguyen TD, Pogash TJ, Santucci-Pereira J, Russo J. Epigenetic reprogramming of epithelial mesenchymal transition in triple negative breast cancer cells with DNA methyltransferase and histone deacetylase inhibitors. J Exp Clin Cancer Res. 2018;37(1):314. https://doi.org/10.1186/s13046-018-0988-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Sood S, Patel FD, Ghosh S, Arora A, Dhaliwal LK, Srinivasan R. Epigenetic alteration by DNA methylation of ESR1, MYOD1 and hTERT gene promoters is useful for prediction of response in patients of locally advanced invasive cervical carcinoma treated by chemoradiation. Clin Oncol (R Coll Radiol). 2015;27(12):720–7. https://doi.org/10.1016/j.clon.2015.08.001.

    Article  CAS  Google Scholar 

  61. Chen CC, Lee KD, Pai MY, Chu PY, Hsu CC, Chiu CC, et al. Changes in DNA methylation are associated with the development of drug resistance in cervical cancer cells. Cancer Cell Int. 2015;15:98. https://doi.org/10.1186/s12935-015-0248-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Huang Z, Zhang S, Shen Y, Liu W, Long J, Zhou S. Influence of MDR1 methylation on the curative effect of interventional embolism chemotherapy for cervical cancer. Ther Clin Risk Manag. 2016;12:217–23. https://doi.org/10.2147/TCRM.S95453.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. He T, Zhang M, Zheng R, Zheng S, Linghu E, Herman JG, et al. Methylation of SLFN11 is a marker of poor prognosis and cisplatin resistance in colorectal cancer. Epigenomics. 2017;9(6):849–62. https://doi.org/10.2217/epi-2017-0019.

    Article  CAS  PubMed  Google Scholar 

  64. Kang KA, Piao MJ, Ryu YS, Kang HK, Chang WY, Keum YS, et al. Interaction of DNA demethylase and histone methyltransferase upregulates Nrf2 in 5-fluorouracil-resistant colon cancer cells. Oncotarget. 2016;7(26):40594–620. https://doi.org/10.18632/oncotarget.9745.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Fesler A, Guo S, Liu H, Wu N, Ju J. Overcoming chemoresistance in cancer stem cells with the help of microRNAs in colorectal cancer. Epigenomics. 2017;9(6):793–6. https://doi.org/10.2217/epi-2017-0041.

    Article  CAS  PubMed  Google Scholar 

  66. Miyaki Y, Suzuki K, Koizumi K, Kato T, Saito M, Kamiyama H, et al. Identification of a potent epigenetic biomarker for resistance to camptothecin and poor outcome to irinotecan-based chemotherapy in colon cancer. Int J Oncol. 2012;40(1):217–26. https://doi.org/10.3892/ijo.2011.1189.

    Article  CAS  PubMed  Google Scholar 

  67. Garcia-Solano J, Turpin MC, Torres-Moreno D, Huertas-Lopez F, Tuomisto A, Makinen MJ, et al. Two histologically colorectal carcinomas subsets from the serrated pathway show different methylome signatures and diagnostic biomarkers. Clin Epigenetics. 2018;10(1):141. https://doi.org/10.1186/s13148-018-0571-3.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Ellis HP, Greenslade M, Powell B, Spiteri I, Sottoriva A, Kurian KM. Current challenges in glioblastoma: intratumour heterogeneity, residual disease, and models to predict disease recurrence. Front Oncol. 2015;5:251. https://doi.org/10.3389/fonc.2015.00251.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352(10):997–1003. https://doi.org/10.1056/NEJMoa043331.

    Article  CAS  PubMed  Google Scholar 

  70. Banelli B, Carra E, Barbieri F, Wurth R, Parodi F, Pattarozzi A, et al. The histone demethylase KDM5A is a key factor for the resistance to temozolomide in glioblastoma. Cell Cycle. 2015;14(21):3418–29. https://doi.org/10.1080/15384101.2015.1090063.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Malhotra M, Sekar TV, Ananta JS, Devulapally R, Afjei R, Babikir HA, et al. Targeted nanoparticle delivery of therapeutic antisense microRNAs presensitizes glioblastoma cells to lower effective doses of temozolomide in vitro and in a mouse model. Oncotarget. 2018;9(30):21478–94. https://doi.org/10.18632/oncotarget.25135.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Cheng ZX, Yin WB, Wang ZY. MicroRNA-132 induces temozolomide resistance and promotes the formation of cancer stem cell phenotypes by targeting tumor suppressor candidate 3 in glioblastoma. Int J Mol Med. 2017;40(5):1307–14. https://doi.org/10.3892/ijmm.2017.3124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Chen Y, Li R, Pan M, Shi Z, Yan W, Liu N, et al. MiR-181b modulates chemosensitivity of glioblastoma multiforme cells to temozolomide by targeting the epidermal growth factor receptor. J Neurooncol. 2017;133(3):477–85. https://doi.org/10.1007/s11060-017-2463-3.

    Article  CAS  PubMed  Google Scholar 

  74. Banelli B, Daga A, Forlani A, Allemanni G, Marubbi D, Pistillo MP, et al. Small molecules targeting histone demethylase genes (KDMs) inhibit growth of temozolomide-resistant glioblastoma cells. Oncotarget. 2017;8(21):34896–910. https://doi.org/10.18632/oncotarget.16820.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Hong X, Kim ES, Guo H. Epigenetic regulation of hepatitis B virus covalently closed circular DNA: implications for epigenetic therapy against chronic hepatitis B. Hepatology. 2017;66(6):2066–77. https://doi.org/10.1002/hep.29479.

    Article  CAS  PubMed  Google Scholar 

  76. Jin X, Tian S, Li P. Histone acetyltransferase 1 promotes cell proliferation and induces cisplatin resistance in hepatocellular carcinoma. Oncol Res. 2017;25(6):939–46. https://doi.org/10.3727/096504016X14809827856524.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Xue F, Liang Y, Li Z, Liu Y, Zhang H, Wen Y, et al. MicroRNA-9 enhances sensitivity to cetuximab in epithelial phenotype hepatocellular carcinoma cells through regulation of the eukaryotic translation initiation factor 5A-2. Oncol Lett. 2018;15(1):813–20. https://doi.org/10.3892/ol.2017.7399.

    Article  CAS  PubMed  Google Scholar 

  78. Yahya SMM, Fathy SA, El-Khayat ZA, El-Toukhy SE, Hamed AR, Hegazy MGA, et al. Possible role of microRNA-122 in modulating multidrug resistance of hepatocellular carcinoma. Indian J Clin Biochem. 2018;33(1):21–30. https://doi.org/10.1007/s12291-017-0651-8.

    Article  CAS  PubMed  Google Scholar 

  79. Niu L, Liu L, Yang S, Ren J, Lai PBS, Chen GG. New insights into sorafenib resistance in hepatocellular carcinoma: responsible mechanisms and promising strategies. Biochim Biophys Acta. 2017;1868(2):564–70. https://doi.org/10.1016/j.bbcan.2017.10.002.

    Article  CAS  Google Scholar 

  80. Tang B, Zhang Y, Liang R, Gao Z, Sun D, Wang L. RNAi-mediated EZH2 depletion decreases MDR1 expression and sensitizes multidrug-resistant hepatocellular carcinoma cells to chemotherapy. Oncol Rep. 2013;29(3):1037–42. https://doi.org/10.3892/or.2013.2222.

    Article  CAS  PubMed  Google Scholar 

  81. Heuser M, Yun H, Thol F. Epigenetics in myelodysplastic syndromes. Semin Cancer Biol. 2018;51:170–9. https://doi.org/10.1016/j.semcancer.2017.07.009.

    Article  CAS  PubMed  Google Scholar 

  82. Cancer Genome Atlas Research Network, Ley TJ, Miller C, Ding L, Raphael BJ, Mungall AJ, et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368(22):2059–74. https://doi.org/10.1056/NEJMoa1301689.

    Article  CAS  Google Scholar 

  83. Kuiper JL, Heideman DA, Thunnissen E, Paul MA, van Wijk AW, Postmus PE, et al. Incidence of T790M mutation in (sequential) rebiopsies in EGFR-mutated NSCLC-patients. Lung Cancer. 2014;85(1):19–24. https://doi.org/10.1016/j.lungcan.2014.03.016.

    Article  CAS  PubMed  Google Scholar 

  84. Park C, Lee IJ, Jang SH, Lee JW. Factors affecting tumor recurrence after curative surgery for NSCLC: impacts of lymphovascular invasion on early tumor recurrence. J Thorac Dis. 2014;6(10):1420–8. https://doi.org/10.3978/j.issn.2072-1439.2014.09.31.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Topper MJ, Vaz M, Chiappinelli KB, DeStefano Shields CE, Niknafs N, Yen RC, et al. Epigenetic therapy ties MYC depletion to reversing immune evasion and treating lung cancer. Cell. 2017;171(6):1284–300 e21. https://doi.org/10.1016/j.cell.2017.10.022.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Zhang S, Wu K, Feng J, Wu Z, Deng Q, Guo C, et al. Epigenetic therapy potential of suberoylanilide hydroxamic acid on invasive human non-small cell lung cancer cells. Oncotarget. 2016;7(42):68768–80. https://doi.org/10.18632/oncotarget.11967.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Taguchi YH, Iwadate M, Umeyama H. SFRP1 is a possible candidate for epigenetic therapy in non-small cell lung cancer. BMC Med Genomics. 2016;9(Suppl 1):28. https://doi.org/10.1186/s12920-016-0196-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Duruisseaux M, Esteller M. Lung cancer epigenetics: from knowledge to applications. Semin Cancer Biol. 2018;51:116–28. https://doi.org/10.1016/j.semcancer.2017.09.005.

    Article  CAS  PubMed  Google Scholar 

  89. Armas-Lopez L, Pina-Sanchez P, Arrieta O, de Alba EG, Ortiz-Quintero B, Santillan-Doherty P, et al. Epigenomic study identifies a novel mesenchyme homeobox2-GLI1 transcription axis involved in cancer drug resistance, overall survival and therapy prognosis in lung cancer patients. Oncotarget. 2017;8(40):67056–81. https://doi.org/10.18632/oncotarget.17715.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Zakharia Y, Monga V, Swami U, Bossler AD, Freesmeier M, Frees M, et al. Targeting epigenetics for treatment of BRAF mutated metastatic melanoma with decitabine in combination with vemurafenib: a phase lb study. Oncotarget. 2017;8(51):89182–93. https://doi.org/10.18632/oncotarget.21269.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Fu S, Wu H, Zhang H, Lian CG, Lu Q. DNA methylation/hydroxymethylation in melanoma. Oncotarget. 2017;8(44):78163–73. https://doi.org/10.18632/oncotarget.18293.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Kapoor A, Goldberg MS, Cumberland LK, Ratnakumar K, Segura MF, Emanuel PO, et al. The histone variant macroH2A suppresses melanoma progression through regulation of CDK8. Nature. 2010;468(7327):1105–9. https://doi.org/10.1038/nature09590.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Issa ME, Takhsha FS, Chirumamilla CS, Perez-Novo C, Vanden Berghe W, Cuendet M. Epigenetic strategies to reverse drug resistance in heterogeneous multiple myeloma. Clin Epigenetics. 2017;9:17. https://doi.org/10.1186/s13148-017-0319-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Lapinska K, Faria G, McGonagle S, Macumber KM, Heerboth S, Sarkar S. Cancer progenitor cells: the result of an epigenetic event? Anticancer Res. 2018;38(1):1–6. https://doi.org/10.21873/anticanres.12184.

    Article  CAS  PubMed  Google Scholar 

  95. Lapinskas T, Pedrizzetti G, Stoiber L, Dungen HD, Edelmann F, Pieske B, et al. The intraventricular hemodynamic forces estimated using routine CMR cine images: a new marker of the failing heart. JACC Cardiovasc Imaging. 2019;12(2):377–9. https://doi.org/10.1016/j.jcmg.2018.08.012.

    Article  PubMed  Google Scholar 

  96. Leary M, Heerboth S, Lapinska K, Sarkar S. Sensitization of drug resistant cancer cells: a matter of combination therapy. Cancers (Basel). 2018;10(12) https://doi.org/10.3390/cancers10120483.

    Article  PubMed Central  Google Scholar 

  97. Abdul QA, Yu BP, Chung HY, Jung HA, Choi JS. Epigenetic modifications of gene expression by lifestyle and environment. Arch Pharm Res. 2017;40(11):1219–37. https://doi.org/10.1007/s12272-017-0973-3.

    Article  CAS  PubMed  Google Scholar 

  98. Chung H, Sidhu KS. Epigenetic modifications of embryonic stem cells: current trends and relevance in developing regenerative medicine. Stem Cells Cloning. 2008;1:11–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Bayat S, Shekari Khaniani M, Choupani J, Alivand MR, Mansoori Derakhshan S. HDACis (class I), cancer stem cell, and phytochemicals: cancer therapy and prevention implications. Biomed Pharmacother. 2018;97:1445–53. https://doi.org/10.1016/j.biopha.2017.11.065.

    Article  CAS  PubMed  Google Scholar 

  100. Munoz P, Iliou MS, Esteller M. Epigenetic alterations involved in cancer stem cell reprogramming. Mol Oncol. 2012;6(6):620–36. https://doi.org/10.1016/j.molonc.2012.10.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Sui H, Fan ZZ, Li Q. Signal transduction pathways and transcriptional mechanisms of ABCB1/Pgp-mediated multiple drug resistance in human cancer cells. J Int Med Res. 2012;40(2):426–35. https://doi.org/10.1177/147323001204000204.

    Article  CAS  PubMed  Google Scholar 

  102. McIntosh K, Balch C, Tiwari AK. Tackling multidrug resistance mediated by efflux transporters in tumor-initiating cells. Expert Opin Drug Metab Toxicol. 2016;12(6):633–44. https://doi.org/10.1080/17425255.2016.1179280.

    Article  CAS  PubMed  Google Scholar 

  103. Geng S, Guo Y, Wang Q, Li L, Wang J. Cancer stem-like cells enriched with CD29 and CD44 markers exhibit molecular characteristics with epithelial-mesenchymal transition in squamous cell carcinoma. Arch Dermatol Res. 2013;305(1):35–47. https://doi.org/10.1007/s00403-012-1260-2.

    Article  CAS  PubMed  Google Scholar 

  104. Piao JH, Wang Y, Duncan ID. CD44 is required for the migration of transplanted oligodendrocyte progenitor cells to focal inflammatory demyelinating lesions in the spinal cord. Glia. 2013;61(3):361–7. https://doi.org/10.1002/glia.22438.

    Article  PubMed  Google Scholar 

  105. Wang C, Xie J, Guo J, Manning HC, Gore JC, Guo N. Evaluation of CD44 and CD133 as cancer stem cell markers for colorectal cancer. Oncol Rep. 2012;28(4):1301–8. https://doi.org/10.3892/or.2012.1951.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Kaiser MF, Johnson DC, Wu P, Walker BA, Brioli A, Mirabella F, et al. Global methylation analysis identifies prognostically important epigenetically inactivated tumor suppressor genes in multiple myeloma. Blood. 2013;122(2):219–26. https://doi.org/10.1182/blood-2013-03-487884.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Fernandez de Larrea C, Martin-Antonio B, Cibeira MT, Navarro A, Tovar N, Diaz T, et al. Impact of global and gene-specific DNA methylation pattern in relapsed multiple myeloma patients treated with bortezomib. Leuk Res. 2013;37(6):641–6. https://doi.org/10.1016/j.leukres.2013.01.013.

    Article  CAS  PubMed  Google Scholar 

  108. Heuck CJ, Mehta J, Bhagat T, Gundabolu K, Yu Y, Khan S, et al. Myeloma is characterized by stage-specific alterations in DNA methylation that occur early during myelomagenesis. J Immunol. 2013;190(6):2966–75. https://doi.org/10.4049/jimmunol.1202493.

    Article  CAS  PubMed  Google Scholar 

  109. Boscolo-Rizzo P, Bussu F. Beware of the dangers along the path towards the diagnosis of HPV-driven oropharyngeal squamous cell carcinoma. Acta Otorhinolaryngol Ital. 2017;37(1):63–4. https://doi.org/10.14639/0392-100X-1323.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Boscolo-Rizzo P, Furlan C, Lupato V, Polesel J, Fratta E. Novel insights into epigenetic drivers of oropharyngeal squamous cell carcinoma: role of HPV and lifestyle factors. Clin Epigenetics. 2017;9:124. https://doi.org/10.1186/s13148-017-0424-5.

    Article  PubMed  PubMed Central  Google Scholar 

  111. Schroeder L, Boscolo-Rizzo P, Dal Cin E, Romeo S, Baboci L, Dyckhoff G, et al. Human papillomavirus as prognostic marker with rising prevalence in neck squamous cell carcinoma of unknown primary: a retrospective multicentre study. Eur J Cancer. 2017;74:73–81. https://doi.org/10.1016/j.ejca.2016.12.020.

    Article  PubMed  Google Scholar 

  112. Anderson KS, Dahlstrom KR, Cheng JN, Alam R, Li G, Wei Q, et al. HPV16 antibodies as risk factors for oropharyngeal cancer and their association with tumor HPV and smoking status. Oral Oncol. 2015;51(7):662–7. https://doi.org/10.1016/j.oraloncology.2015.04.011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Dahlstrom KR, Bell D, Hanby D, Li G, Wang LE, Wei Q, et al. Socioeconomic characteristics of patients with oropharyngeal carcinoma according to tumor HPV status, patient smoking status, and sexual behavior. Oral Oncol. 2015;51(9):832–8. https://doi.org/10.1016/j.oraloncology.2015.06.005.

    Article  PubMed  PubMed Central  Google Scholar 

  114. Dahlstrom KR, Li G, Hussey CS, Vo JT, Wei Q, Zhao C, et al. Circulating human papillomavirus DNA as a marker for disease extent and recurrence among patients with oropharyngeal cancer. Cancer. 2015;121(19):3455–64. https://doi.org/10.1002/cncr.29538.

    Article  CAS  PubMed  Google Scholar 

  115. Chen X, Liu L, Mims J, Punska EC, Williams KE, Zhao W, et al. Analysis of DNA methylation and gene expression in radiation-resistant head and neck tumors. Epigenetics. 2015;10(6):545–61. https://doi.org/10.1080/15592294.2015.1048953.

    Article  PubMed  PubMed Central  Google Scholar 

  116. Lin HY, Huang TH, Chan MW. Aberrant epigenetic modifications in radiation-resistant head and neck cancers. Methods Mol Biol. 2015;1238:321–32. https://doi.org/10.1007/978-1-4939-1804-1_17.

    Article  PubMed  Google Scholar 

  117. Furlan C, Polesel J, Barzan L, Franchin G, Sulfaro S, Romeo S, et al. Prognostic significance of LINE-1 hypomethylation in oropharyngeal squamous cell carcinoma. Clin Epigenetics. 2017;9:58. https://doi.org/10.1186/s13148-017-0357-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Stephen JK, Worsham MJ. Human papilloma virus (HPV) modulation of the HNSCC epigenome. Methods Mol Biol. 2015;1238:369–79. https://doi.org/10.1007/978-1-4939-1804-1_20.

    Article  PubMed  Google Scholar 

  119. Idris S, Lindsay C, Kostiuk M, Andrews C, Cote DW, O’Connell DA, et al. Investigation of EZH2 pathways for novel epigenetic treatment strategies in oropharyngeal cancer. J Otolaryngol Head Neck Surg. 2016;45(1):54. https://doi.org/10.1186/s40463-016-0168-9.

    Article  PubMed  PubMed Central  Google Scholar 

  120. Lindsay CD, Kostiuk MA, Harris J, O’Connell DA, Seikaly H, Biron VL. Efficacy of EZH2 inhibitory drugs in human papillomavirus-positive and human papillomavirus-negative oropharyngeal squamous cell carcinomas. Clin Epigenetics. 2017;9:95. https://doi.org/10.1186/s13148-017-0390-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Balch C, Huang TH, Brown R, Nephew KP. The epigenetics of ovarian cancer drug resistance and resensitization. Am J Obstet Gynecol. 2004;191(5):1552–72. https://doi.org/10.1016/j.ajog.2004.05.025.

    Article  CAS  PubMed  Google Scholar 

  122. Enuka Y, Feldman ME, Chowdhury A, Srivastava S, Lindzen M, Sas-Chen A, et al. Epigenetic mechanisms underlie the crosstalk between growth factors and a steroid hormone. Nucleic Acids Res. 2017;45(22):12681–99. https://doi.org/10.1093/nar/gkx865.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Klymenko Y, Nephew KP. Epigenetic crosstalk between the tumor microenvironment and ovarian cancer cells: a therapeutic road less traveled. Cancers (Basel). 2018;10(9) https://doi.org/10.3390/cancers10090295.

    Article  PubMed Central  Google Scholar 

  124. Latcheva NK, Viveiros JM, Waddell EA, Nguyen PTT, Liebl FLW, Marenda DR. Epigenetic crosstalk: pharmacological inhibition of HDACs can rescue defective synaptic morphology and neurotransmission phenotypes associated with loss of the chromatin reader Kismet. Mol Cell Neurosci. 2018;87:77–85. https://doi.org/10.1016/j.mcn.2017.11.007.

    Article  CAS  PubMed  Google Scholar 

  125. Liu D, Zhang XX, Li MC, Cao CH, Wan DY, Xi BX, et al. C/EBPbeta enhances platinum resistance of ovarian cancer cells by reprogramming H3K79 methylation. Nat Commun. 2018;9(1):1739. https://doi.org/10.1038/s41467-018-03590-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Cacan E. Epigenetic-mediated immune suppression of positive co-stimulatory molecules in chemoresistant ovarian cancer cells. Cell Biol Int. 2017;41(3):328–39. https://doi.org/10.1002/cbin.10729.

    Article  CAS  PubMed  Google Scholar 

  127. Kandel P, Wallace MB, Stauffer J, Bolan C, Raimondo M, Woodward TA, et al. Survival of patients with oligometastatic pancreatic ductal adenocarcinoma treated with combined modality treatment including surgical resection: a pilot study. J Pancreat Cancer. 2018;4(1):88–94. https://doi.org/10.1089/pancan.2018.0011.

    Article  PubMed  PubMed Central  Google Scholar 

  128. Cai MH, Xu XG, Yan SL, Sun Z, Ying Y, Wang BK, et al. Depletion of HDAC1, 7 and 8 by histone deacetylase inhibition confers elimination of pancreatic cancer stem cells in combination with gemcitabine. Sci Rep. 2018;8(1):1621. https://doi.org/10.1038/s41598-018-20004-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Ma YT, Leonard SM, Gordon N, Anderton J, James C, Huen D, et al. Use of a genome-wide haploid genetic screen to identify treatment predicting factors: a proof-of-principle study in pancreatic cancer. Oncotarget. 2017;8(38):63635–45. https://doi.org/10.18632/oncotarget.18879.

    Article  PubMed  PubMed Central  Google Scholar 

  130. Kwon HM, Kang EJ, Kang K, Kim SD, Yang K, Yi JM. Combinatorial effects of an epigenetic inhibitor and ionizing radiation contribute to targeted elimination of pancreatic cancer stem cell. Oncotarget. 2017;8(51):89005–20. https://doi.org/10.18632/oncotarget.21642.

    Article  PubMed  PubMed Central  Google Scholar 

  131. Stangelberger A, Waldert M, Djavan B. Prostate cancer in elderly men. Rev Urol. 2008;10(2):111–9.

    PubMed  PubMed Central  Google Scholar 

  132. Vatandoust S, Kichenadasse G, O’Callaghan M, Vincent AD, Kopsaftis T, Walsh S, et al. Localised prostate cancer in elderly men aged 80-89 years, findings from a population-based registry. BJU Int. 2018;121 Suppl 3:48–54. https://doi.org/10.1111/bju.14228.

    Article  PubMed  Google Scholar 

  133. Sun Y, Wang BE, Leong KG, Yue P, Li L, Jhunjhunwala S, et al. Androgen deprivation causes epithelial-mesenchymal transition in the prostate: implications for androgen-deprivation therapy. Cancer Res. 2012;72(2):527–36. https://doi.org/10.1158/0008-5472.CAN-11-3004.

    Article  CAS  PubMed  Google Scholar 

  134. Gu P, Chen X, Xie R, Han J, Xie W, Wang B, et al. lncRNA HOXD-AS1 regulates proliferation and chemo-resistance of castration-resistant prostate cancer via recruiting WDR5. Mol Ther. 2017;25(8):1959–73. https://doi.org/10.1016/j.ymthe.2017.04.016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Katzenwadel A, Wolf P. Androgen deprivation of prostate cancer: leading to a therapeutic dead end. Cancer Lett. 2015;367(1):12–7. https://doi.org/10.1016/j.canlet.2015.06.021.

    Article  CAS  PubMed  Google Scholar 

  136. Yarmishyn AA, Batagov AO, Tan JZ, Sundaram GM, Sampath P, Kuznetsov VA, et al. HOXD-AS1 is a novel lncRNA encoded in HOXD cluster and a marker of neuroblastoma progression revealed via integrative analysis of noncoding transcriptome. BMC Genomics. 2014;15(Suppl 9):S7. https://doi.org/10.1186/1471-2164-15-S9-S7.

    Article  PubMed  PubMed Central  Google Scholar 

  137. Yang YW, Flynn RA, Chen Y, Qu K, Wan B, Wang KC, et al. Essential role of lncRNA binding for WDR5 maintenance of active chromatin and embryonic stem cell pluripotency. Elife. 2014;3:e02046. https://doi.org/10.7554/eLife.02046.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Kim JY, Banerjee T, Vinckevicius A, Luo Q, Parker JB, Baker MR, et al. A role for WDR5 in integrating threonine 11 phosphorylation to lysine 4 methylation on histone H3 during androgen signaling and in prostate cancer. Mol Cell. 2014;54(4):613–25. https://doi.org/10.1016/j.molcel.2014.03.043.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Brikun I, Nusskern D, Decatus A, Harvey E, Li L, Freije D. A panel of DNA methylation markers for the detection of prostate cancer from FV and DRE urine DNA. Clin Epigenetics. 2018;10:91. https://doi.org/10.1186/s13148-018-0524-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Kuusk T, De Bruijn R, Brouwer OR, De Jong J, Donswijk M, Hendricksen K, et al. Outcome of sentinel lymph node biopsy in patients with clinically non-metastatic renal cell carcinoma. Scand J Urol. 2018;52(5–6):411–8. https://doi.org/10.1080/21681805.2018.1531057.

    Article  CAS  PubMed  Google Scholar 

  141. Santoni M, Piva F, De Giorgi U, Mosca A, Basso U, Santini D, et al. Autophagic gene polymorphisms in liquid biopsies and outcome of patients with metastatic clear cell renal cell carcinoma. Anticancer Res. 2018;38(10):5773–82. https://doi.org/10.21873/anticanres.12916.

    Article  CAS  PubMed  Google Scholar 

  142. Saeednejad Zanjani L, Madjd Z, Abolhasani M, Rasti A, Shariftabrizi A, Mehrazma M, et al. Human telomerase reverse transcriptase protein expression predicts tumour aggressiveness and survival in patients with clear cell renal cell carcinoma. Pathology. 2019;51(1):21–31. https://doi.org/10.1016/j.pathol.2018.08.019.

    Article  CAS  PubMed  Google Scholar 

  143. Winter S, Fisel P, Buttner F, Nies AT, Stenzl A, Bedke J, et al. Comment on “Epigenetic activation of the drug transporter OCT2 sensitizes renal cell carcinoma to oxaliplatin”. Sci Transl Med. 2017;9(391) https://doi.org/10.1126/scitranslmed.aal2439.

    Article  PubMed  Google Scholar 

  144. Zheng X, Liu Y, Yu Q, Wang H, Tan F, Zhu Q, et al. Response to comment on “Epigenetic activation of the drug transporter OCT2 sensitizes renal cell carcinoma to oxaliplatin”. Sci Transl Med. 2017;9(391) https://doi.org/10.1126/scitranslmed.aam6298.

    Article  PubMed  Google Scholar 

  145. Liu Y, Zheng X, Yu Q, Wang H, Tan F, Zhu Q, et al. Epigenetic activation of the drug transporter OCT2 sensitizes renal cell carcinoma to oxaliplatin. Sci Transl Med. 2016;8(348):348ra97. https://doi.org/10.1126/scitranslmed.aaf3124.

    Article  CAS  PubMed  Google Scholar 

  146. Balasubramanian D, Akhtar-Zaidi B, Song L, Bartels CF, Veigl M, Beard L, et al. H3K4me3 inversely correlates with DNA methylation at a large class of non-CpG-island-containing start sites. Genome Med. 2012;4(5):47. https://doi.org/10.1186/gm346.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Perini G, Diolaiti D, Porro A, Della Valle G. In vivo transcriptional regulation of N-Myc target genes is controlled by E-box methylation. Proc Natl Acad Sci U S A. 2005;102(34):12117–22. https://doi.org/10.1073/pnas.0409097102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Xi W, Chen X, Sun J, Wang W, Huo Y, Zheng G, et al. Combined treatment with valproic acid and 5-Aza-2′-deoxycytidine synergistically inhibits human clear cell renal cell carcinoma growth and migration. Med Sci Monit. 2018;24:1034–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Bodnar L, Stec R, Cierniak S, Synowiec A, Wcislo G, Jesiotr M, et al. Role of WNT/beta-catenin pathway as potential prognostic and predictive factors in renal cell cancer patients treated with everolimus in the second and subsequent lines. Clin Genitourin Cancer. 2018;16(4):257–65. https://doi.org/10.1016/j.clgc.2018.01.008.

    Article  PubMed  Google Scholar 

  150. Li YL, Jin YF, Liu XX, Li HJ. A comprehensive analysis of Wnt/beta-catenin signaling pathway-related genes and crosstalk pathways in the treatment of As2O3 in renal cancer. Ren Fail. 2018;40(1):331–9. https://doi.org/10.1080/0886022X.2018.1456461.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Schodel J, Grampp S, Maher ER, Moch H, Ratcliffe PJ, Russo P, et al. Hypoxia, hypoxia-inducible transcription factors, and renal cancer. Eur Urol. 2016;69(4):646–57. https://doi.org/10.1016/j.eururo.2015.08.007.

    Article  CAS  PubMed  Google Scholar 

  152. Lin HW, Fu CF, Chang MC, Lu TP, Lin HP, Chiang YC, et al. CDH1, DLEC1 and SFRP5 methylation panel as a prognostic marker for advanced epithelial ovarian cancer. Epigenomics. 2018;10(11):1397–413. https://doi.org/10.2217/epi-2018-0035.

    Article  CAS  PubMed  Google Scholar 

  153. Ge G, Peng D, Xu Z, Guan B, Xin Z, He Q, et al. Restoration of 5-hydroxymethylcytosine by ascorbate blocks kidney tumour growth. EMBO Rep. 2018;19(8) https://doi.org/10.15252/embr.201745401.

    Article  PubMed  PubMed Central  Google Scholar 

  154. Yeon A, You S, Kim M, Gupta A, Park MH, Weisenberger DJ, et al. Rewiring of cisplatin-resistant bladder cancer cells through epigenetic regulation of genes involved in amino acid metabolism. Theranostics. 2018;8(16):4520–34. https://doi.org/10.7150/thno.25130.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Khandelwal M, Anand V, Appunni S, Seth A, Singh P, Mathur S, et al. Decitabine augments cytotoxicity of cisplatin and doxorubicin to bladder cancer cells by activating hippo pathway through RASSF1A. Mol Cell Biochem. 2018;446(1–2):105–14. https://doi.org/10.1007/s11010-018-3278-z.

    Article  CAS  PubMed  Google Scholar 

  156. Szablewski V, Bret C, Kassambara A, Devin J, Cartron G, Costes-Martineau V, et al. An epigenetic regulator-related score (EpiScore) predicts survival in patients with diffuse large B cell lymphoma and identifies patients who may benefit from epigenetic therapy. Oncotarget. 2018;9(27):19079–99. https://doi.org/10.18632/oncotarget.24901.

    Article  PubMed  PubMed Central  Google Scholar 

  157. Wilson S, Filipp FV. A network of epigenomic and transcriptional cooperation encompassing an epigenomic master regulator in cancer. NPJ Syst Biol Appl. 2018;4:24. https://doi.org/10.1038/s41540-018-0061-4.

    Article  PubMed  PubMed Central  Google Scholar 

  158. Liu B, Wang T, Wang H, Zhang L, Xu F, Fang R, et al. Oncoprotein HBXIP enhances HOXB13 acetylation and co-activates HOXB13 to confer tamoxifen resistance in breast cancer. J Hematol Oncol. 2018;11(1):26. https://doi.org/10.1186/s13045-018-0577-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Ojo D, Lin X, Wu Y, Cockburn J, Bane A, Tang D. Polycomb complex protein BMI1 confers resistance to tamoxifen in estrogen receptor positive breast cancer. Cancer Lett. 2018;426:4–13. https://doi.org/10.1016/j.canlet.2018.03.048.

    Article  CAS  PubMed  Google Scholar 

  160. Wu Y, Zhang Z, Cenciarini ME, Proietti CJ, Amasino M, Hong T, et al. Tamoxifen resistance in breast cancer is regulated by the EZH2-ERalpha-GREB1 transcriptional axis. Cancer Res. 2018;78(3):671–84. https://doi.org/10.1158/0008-5472.CAN-17-1327.

    Article  CAS  PubMed  Google Scholar 

  161. Yang H, Bueso-Ramos C, DiNardo C, Estecio MR, Davanlou M, Geng QR, et al. Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents. Leukemia. 2014;28(6):1280–8. https://doi.org/10.1038/leu.2013.355.

    Article  CAS  PubMed  Google Scholar 

  162. Hogg SJ, Vervoort SJ, Deswal S, Ott CJ, Li J, Cluse LA, et al. BET-bromodomain inhibitors engage the host immune system and regulate expression of the immune checkpoint ligand PD-L1. Cell Rep. 2017;18(9):2162–74. https://doi.org/10.1016/j.celrep.2017.02.011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Lee HZ, Kwitkowski VE, Del Valle PL, Ricci MS, Saber H, Habtemariam BA, et al. FDA approval: belinostat for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma. Clin Cancer Res. 2015;21(12):2666–70. https://doi.org/10.1158/1078-0432.CCR-14-3119.

    Article  CAS  PubMed  Google Scholar 

  164. Raynal NJ, Da Costa EM, Lee JT, Gharibyan V, Ahmed S, Zhang H, et al. Repositioning FDA-approved drugs in combination with epigenetic drugs to reprogram colon cancer epigenome. Mol Cancer Ther. 2017;16(2):397–407. https://doi.org/10.1158/1535-7163.MCT-16-0588.

    Article  CAS  PubMed  Google Scholar 

  165. Abdelfatah E, Kerner Z, Nanda N, Ahuja N. Epigenetic therapy in gastrointestinal cancer: the right combination. Therap Adv Gastroenterol. 2016;9(4):560–79. https://doi.org/10.1177/1756283X16644247.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Conte M, De Palma R, Altucci L. HDAC inhibitors as epigenetic regulators for cancer immunotherapy. Int J Biochem Cell Biol. 2018;98:65–74. https://doi.org/10.1016/j.biocel.2018.03.004.

    Article  CAS  PubMed  Google Scholar 

  167. Zhao L, Duan YT, Lu P, Zhang ZJ, Zheng XK, Wang JL, et al. Epigenetic targets and their inhibitors in cancer therapy. Curr Top Med Chem. 2018;18(28):2395–419. https://doi.org/10.2174/1568026619666181224095449.

    Article  CAS  PubMed  Google Scholar 

  168. Verma M, Banerjee HN. Epigenetic inhibitors. Methods Mol Biol. 2015;1238:469–85. https://doi.org/10.1007/978-1-4939-1804-1_24.

    Article  PubMed  Google Scholar 

  169. Verma SK. Recent progress in the discovery of epigenetic inhibitors for the treatment of cancer. Methods Mol Biol. 2015;1238:677–88. https://doi.org/10.1007/978-1-4939-1804-1_35.

    Article  PubMed  Google Scholar 

Download references

Financial Disclosure

There is no financial conflict.

Author information

Authors and Affiliations

  1. Methods and Technologies Branch, Epidemiology and Genomics Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Mukesh Verma

  2. Department of Physiology, National University of Singapore, Singapore, Singapore

    Vineet Kumar

Authors
  1. Mukesh Verma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vineet Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Mukesh Verma or Vineet Kumar .

Editor information

Editors and Affiliations

  1. Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada

    Myron R. Szewczuk

  2. Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada

    Bessi Qorri

  3. Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada

    Manpreet Sambi

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Verma, M., Kumar, V. (2019). Targeting Epigenetic Regulators in Cancer to Overcome Resistance to Targeted Therapy. In: Szewczuk, M., Qorri, B., Sambi, M. (eds) Current Applications for Overcoming Resistance to Targeted Therapies. Resistance to Targeted Anti-Cancer Therapeutics, vol 20. Springer, Cham. https://doi.org/10.1007/978-3-030-21477-7_9

Download citation

Publish with us

Policies and ethics

Search

Navigation