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ALKBH5 Holds Prognostic Values and Inhibits the Metastasis of Colon Cancer

  • Peipei Yang
  • Qian Wang
  • Aihua Liu
  • Jun Zhu
  • Jinzhou FengEmail author
Original Article

Abstract

N6-methyladenosine (m6A) demethylase ALKBH5 is best known for modulating transcript modification in plenty of human malignancies, but its role in the progression of colon cancer is not well understood. In the present study, we identified the tumor repressive role of ALKBH5 in colon cancer. ALKBH5 was downregulated in human colon cancer tissues, where its decreased expression significantly correlated with distant metastasis and American Joint Committee on Cancer (AJCC) stage. ALKBH5 was also an independent prognostic indicator of overall survival and disease-free survival in colon cancer patients. Furthermore, functional studies established that overexpression of ALKBH5 inhibited colon cancer cells invasion in vitro and metastasis in vivo. These results indicated that ALKBH5 significantly inhibits tumor progression and serves as a potential therapeutic target for colon cancer.

Keywords

ALKBH5 Colon cancer Invasion Metastasis 

Notes

Acknowledgements

This work was supported by Science and Technology Project of Chongqing Education Committee (No.KJ1600210) and Shandong Province Natural Science Foundation of China (No. ZR2013HL054).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that there is no conflict of interests regarding the publication of this paper.

References

  1. 1.
    Brenner H, Kloor M, Pox CP (2014) Colorectal cancer. Lancet 383:1490–1502CrossRefGoogle Scholar
  2. 2.
    Brody H (2015) Colorectal cancer. Nature 521:S1CrossRefGoogle Scholar
  3. 3.
    Naxerova K, Reiter JG, Brachtel E, Lennerz JK, van de Wetering M, Rowan A, Cai T, Clevers H, Swanton C, Nowak MA, Elledge SJ, Jain RK (2017) Origins of lymphatic and distant metastases in human colorectal cancer. Science 357:55–60CrossRefGoogle Scholar
  4. 4.
    Meyer KD, Saletore Y, Zumbo P, Elemento O, Mason CE, Jaffrey SR (2012) Comprehensive analysis of mRNA methylation reveals enrichment in 3' UTRs and near stop codons. Cell 149:1635–1646CrossRefGoogle Scholar
  5. 5.
    Liu J, Yue Y, Han D, Wang X, Fu Y, Zhang L, Jia G, Yu M, Lu Z, Deng X, Dai Q, Chen W, He C (2014) A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat Chem Biol 10:93–95CrossRefGoogle Scholar
  6. 6.
    Barbieri I, Tzelepis K, Pandolfini L, Shi J, Millán-Zambrano G, Robson SC, Aspris D, Migliori V, Bannister AJ, Han N, de Braekeleer E, Ponstingl H, Hendrick A, Vakoc CR, Vassiliou GS, Kouzarides T (2017) Promoter-bound METTL3 maintains myeloid leukaemia by m(6)A-dependent translation control. Nature 552:126–131CrossRefGoogle Scholar
  7. 7.
    Zhao X, Yang Y, Sun BF, Shi Y, Yang X, Xiao W, Hao YJ, Ping XL, Chen YS, Wang WJ, Jin KX, Wang X, Huang CM, Fu Y, Ge XM, Song SH, Jeong HS, Yanagisawa H, Niu Y, Jia GF, Wu W, Tong WM, Okamoto A, He C, Danielsen JMR, Wang XJ, Yang YG (2014) FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis. Cell Res 24:1403–1419CrossRefGoogle Scholar
  8. 8.
    Dixit D, Xie Q, Rich JN, Zhao JC (2017) Messenger RNA methylation regulates glioblastoma tumorigenesis. Cancer Cell 31:474–475CrossRefGoogle Scholar
  9. 9.
    Zhong X, Yu J, Frazier K et al (2018) Circadian clock regulation of hepatic lipid metabolism by modulation of m(6)A mRNA methylation. Cell Rep 25(1816–1828):e1814Google Scholar
  10. 10.
    Zhao BS, He C (2017) "gamete on" for m(6)A: YTHDF2 exerts essential functions in female fertility. Mol Cell 67:903–905CrossRefGoogle Scholar
  11. 11.
    Geula S, Moshitch-Moshkovitz S, Dominissini D, Mansour AAF, Kol N, Salmon-Divon M, Hershkovitz V, Peer E, Mor N, Manor YS, Ben-Haim MS, Eyal E, Yunger S, Pinto Y, Jaitin DA, Viukov S, Rais Y, Krupalnik V, Chomsky E, Zerbib M, Maza I, Rechavi Y, Massarwa R, Hanna S, Amit I, Levanon EY, Amariglio N, Stern-Ginossar N, Novershtern N, Rechavi G, Hanna JH (2015) Stem cells. m6A mRNA methylation facilitates resolution of naive pluripotency toward differentiation. Science 347:1002–1006CrossRefGoogle Scholar
  12. 12.
    Li HB, Tong J, Zhu S, Batista PJ, Duffy EE, Zhao J, Bailis W, Cao G, Kroehling L, Chen Y, Wang G, Broughton JP, Chen YG, Kluger Y, Simon MD, Chang HY, Yin Z, Flavell RA (2017) m(6)A mRNA methylation controls T cell homeostasis by targeting the IL-7/STAT5/SOCS pathways. Nature 548:338–342CrossRefGoogle Scholar
  13. 13.
    He Y, Hu H, Wang Y, Yuan H, Lu Z, Wu P, Liu D, Tian L, Yin J, Jiang K, Miao Y (2018) ALKBH5 inhibits pancreatic Cancer motility by decreasing long non-coding RNA KCNK15-AS1 methylation. Cellular physiology and biochemistry : international journal of experimental Cell Physiol Biochem 48:838–846Google Scholar
  14. 14.
    Zhang S, Zhao BS, Zhou A et al (2017) M(6)a demethylase ALKBH5 maintains Tumorigenicity of glioblastoma stem-like cells by sustaining FOXM1 expression and cell proliferation program. Cancer Cell 31:591–606 e596CrossRefGoogle Scholar
  15. 15.
    Zhang C, Samanta D, Lu H, Bullen JW, Zhang H, Chen I, He X, Semenza GL (2016) Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m(6)A-demethylation of NANOG mRNA. Proc Natl Acad Sci U S A 113:E2047–E2056CrossRefGoogle Scholar
  16. 16.
    Yue B, Cai D, Liu C, Fang C, Yan D (2016) Linc00152 functions as a competing endogenous RNA to confer oxaliplatin resistance and holds prognostic values in colon cancer. Mol Ther : the journal of the American Society of Gene Therapy 24:2064–2077Google Scholar
  17. 17.
    Yue B, Liu C, Sun H, Liu M, Song C, Cui R, Qiu S, Zhong M (2018) A positive feed-forward loop between LncRNA-CYTOR and Wnt/beta-catenin signaling promotes metastasis of colon cancer. Mol Ther: the journal of the American Society of Gene Therapy 26:1287–1298Google Scholar
  18. 18.
    Fan J, Yan D, Teng M, Tang H, Zhou C, Wang X, Li D, Qiu G, Peng Z (2011) Digital transcript profile analysis with aRNA-LongSAGE validates FERMT1 as a potential novel prognostic marker for colon cancer. Clin Cancer Res: an official journal of the American Association for Cancer Research 17:2908–2918Google Scholar
  19. 19.
    Jiang H, Deng R, Yang X, Shang J, Lu S, Zhao Y, Song K, Liu X, Zhang Q, Chen Y, Chinn YE, Wu G, Li J, Chen G, Yu J, Zhang J (2017) Peptidomimetic inhibitors of APC-Asef interaction block colorectal cancer migration. Nat Chem Biol 13:994–1001CrossRefGoogle Scholar
  20. 20.
    Buhrmann C, Shayan P, Goel A, Shakibaei M (2017) Resveratrol regulates colorectal Cancer cell invasion by modulation of focal adhesion molecules. Nutrients 9Google Scholar
  21. 21.
    Overman MJ, Mcdermott R, Leach JL et al (2017) Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol 18:1182–1191CrossRefGoogle Scholar
  22. 22.
    Li Y, Du Y, Liang X et al (2018) EGFR-targeted liposomal nanohybrid cerasomes: theranostic function and immune checkpoint inhibition in a mouse model of colorectal cancer. Nanoscale 10:16738–16749CrossRefGoogle Scholar
  23. 23.
    Izumi D, Ishimoto T, Miyake K, Eto T, Arima K, Kiyozumi Y, Uchihara T, Kurashige J, Iwatsuki M, Baba Y, Sakamoto Y, Miyamoto Y, Yoshida N, Watanabe M, Goel A, Tan P, Baba H (2017) Colorectal Cancer stem cells acquire Chemoresistance through the upregulation of F-box/WD repeat-containing protein 7 and the consequent degradation of c-Myc. Stem Cells 35:2027–2036CrossRefGoogle Scholar
  24. 24.
    Lian H, Wang QH, Zhu CB, Ma J, Jin WL (2018) Deciphering the Epitranscriptome in Cancer. Trends in Cancer 4:207–221CrossRefGoogle Scholar
  25. 25.
    Guo J, Wu Y, Du J et al (2018) Deregulation of UBE2C-mediated autophagy repression aggravates NSCLC progression. Oncogenesis 7:49CrossRefGoogle Scholar
  26. 26.
    Zhang C, Zhi WI, Lu H, Samanta D, Chen I, Gabrielson E, Semenza GL (2016) Hypoxia-inducible factors regulate pluripotency factor expression by ZNF217- and ALKBH5-mediated modulation of RNA methylation in breast cancer cells. Oncotarget 7:64527–64542Google Scholar

Copyright information

© Arányi Lajos Foundation 2019

Authors and Affiliations

  1. 1.Department of General SurgeryThe First Affiliated Hospital of Anhui University of Science and TechnologyHuainanChina
  2. 2.Department of General SurgeryHuainan First People’s HospitalHuainanChina
  3. 3.Department of Central LaboratoryTaian City Central Hospital, Shandong First Medical University & Shangdong Academy of Medical SciencesTaian,China
  4. 4.Hang Zhou Di’an Medical LaboratoryHangzhouChina
  5. 5.Department of NeurologyThe First Affiliated Hospital of Chongqing Medical UniversityChongqingChina

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