Molecular and Cellular Biochemistry

, Volume 361, Issue 1–2, pp 39–45 | Cite as

VPA inhibits breast cancer cell migration by specifically targeting HDAC2 and down-regulating Survivin

  • Lei Zhang
  • Guiying Wang
  • Lin Wang
  • Chenlin Song
  • Ye Leng
  • Xinhua Wang
  • Jiuhong Kang


Cell migration plays major roles in human breast cancer-related death, but the molecular mechanisms remain unclear. Valproic acid (VPA) is a broad-spectrum inhibitor of class I and II histone deacetylases and shows great anticancer activity in a variety of human cancers including breast cancer. In this study, we found that VPA significantly inhibited cell migration but not proliferation of human breast cancer MDA-MB-231 cells. Mechanistic studies found that VPA significantly inhibited the expression of Survivin. Knockdown of Survivin could obviously inhibited cell migration, while over-expression of Survivin markedly rescued the inhibition of VPA on cell migration. Further studies found that knockdown of HDAC2 completely mimicked the effects of VPA on Survivin and cell migration, and over-expression of Survivin could also rescue the effects of HDAC2 knockdown on cell migration. Collectively, these results indicated that HDAC2 may be the specific target of VPA in breast cancer cells, and specific inhibition of HDAC2, especially by small molecular chemicals may lead to less side-effects and provide a better strategy than VPA application for human breast cancer treatment.


Breast cancer Migration Valproic acid HDAC2 Survivin 



This study was supported by grants from the National Natural Science Foundation of China (90919028, 31071306, 31101061, and 30971451), Ministry of Science and Technology (2011CB965100, 2010CB944900, 2010CB945000, 2011CBA01100, and 2011DFA30480), Science and Technology Commission of Shanghai Municipality (09DZ2260100, 11ZR1438500, 11XD1405300), and Program for Young Excellent Talents in Tongji University (2009KJ089).


  1. 1.
    Adams JM, Cory S (1998) The Bcl-2 protein family: arbiters of cell survival. Science 281:1322–1326. doi: 10.1126/science.281.5381.1322 PubMedCrossRefGoogle Scholar
  2. 2.
    Fornaro M, Plescia J, Chheang S et al (2003) Fibronectin protects prostate cancer cells from tumor necrosis factor-alpha-induced apoptosis via the AKT/survivin pathway. J Biol Chem 278:50402–50411. doi: 10.1074/jbc.M307627200 PubMedCrossRefGoogle Scholar
  3. 3.
    Weigelt B, Peterse JL, Van’t Veer LJ (2005) Breast cancer metastasis: markers and models. Nat Rev Cancer 5:591–602. doi: 10.1038/nrc1670 PubMedCrossRefGoogle Scholar
  4. 4.
    Marchion D, Münster P (2007) Development of histone deacetylase inhibitors for cancer treatment. Expert Rev Anticancer Ther 7:583–598. doi: 10.1586/14737140.7.4.583 PubMedCrossRefGoogle Scholar
  5. 5.
    Witt O, Deubzer HE, Milde T et al (2009) HDAC family: what are the cancer relevant targets? Cancer Lett 277:8–21. doi: 10.1016/j.canlet.2008.08.016 PubMedCrossRefGoogle Scholar
  6. 6.
    Mehrotra S, Languino LR, Raskett CM et al (2010) IAP regulation of metastasis. Cancer Cell 17:53–64. doi: 10.1016/j.ccr.2009.11.021 PubMedCrossRefGoogle Scholar
  7. 7.
    Lee CW, Raskett CM, Prudovsky I et al (2008) Molecular dependence of estrogen receptor–negative breast cancer on a notch-survivin signaling axis. Cancer Res 68:5273–5281. doi: 10.1158/0008-5472.CAN-07-6673 PubMedCrossRefGoogle Scholar
  8. 8.
    Harms KL, Chen X et al (2007) Histone deacetylase 2 modulates p53 transcriptional activities through regulation of p53-DNA binding activity. Cancer Res 67:3145–3152. doi: 10.1158/0008-5472.CAN-06-4397 PubMedCrossRefGoogle Scholar
  9. 9.
    Végran F, Boidot R, Oudin C et al (2007) Association of p53 gene alterations with the expression of antiapoptotic survivin splice variants in breast cancer. Oncogene 26:290–297. doi: 10.1038/sj.onc.1209784 PubMedCrossRefGoogle Scholar
  10. 10.
    Gidal BE, Sheth R, Parnell J et al (2003) Evaluation of VPA dose and concentration effects on lamotrigine pharmacokinetics: implications for conversion to lamotrigine monotherapy. Epilepsy Res 57:85–93. doi: 10.1016/j.eplepsyres.2003.09.008 PubMedCrossRefGoogle Scholar
  11. 11.
    Wang GY, Hu XH, Lu CQ et al (2008) Promoter-hypermethylation associated defective expression of E-cadherin in primary non-small cell lung cancer. Lung Cancer 62:162–172. doi: 10.1016/j.lungcan.2008.03.023 PubMedCrossRefGoogle Scholar
  12. 12.
    Huang BH, Laban M, Leung CH et al (2005) Inhibition of histone deacetylase 2 increases apoptosis and p21Cip1/WAF1 expression, independent of histone deacetylase 1. Cell Death Differ 12:395–404. doi: 10.1038/sj.cdd.4401567 PubMedCrossRefGoogle Scholar
  13. 13.
    Song KH, Park YY, Kee HJ et al (2006) Orphan nuclear receptor Nur77 induces zinc finger protein GIOT-1 gene expression, and GIOT-1 acts as a novel corepressor of orphan nuclear receptor SF-1 via recruitment of HDAC2. J Biol Chem 281:15605–15614. doi: 10.1074/jbc.M505937200 PubMedCrossRefGoogle Scholar
  14. 14.
    Fortunati N, Bertino S, Costantino L et al (2008) Valproic acid is a selective anti-proliferative agent in estrogen-sensitive breast cancer cells. Cancer Lett 259:156–164. doi: 10.1016/j.canlet.2007.10.006 PubMedCrossRefGoogle Scholar
  15. 15.
    Ryan BM, O’Donovan N, Duffy MJ (2009) Survivin: a new target for anti-cancer therapy. Cancer Treat Rev 35:553–562. doi: 10.1016/j.ctrv.2009.05.003 PubMedCrossRefGoogle Scholar
  16. 16.
    Zhang XH, Rao M, Loprieato JA et al (2008) Aurora A, aurora B and survivin are novel targets of transcriptional regulation by histone deacetylase inhibitors in non-small cell lung cancer. Cancer Biol Ther 7(9):1388–1397. doi: 10.4161/cbt.7.9.6415 PubMedCrossRefGoogle Scholar
  17. 17.
    Biran A, Brownstein M, Haklai R et al (2011) Downregulation of survivin and aurora A by histone deacetylase and RAS inhibitors: a new drug combination for cancer therapy. Int J Cancer 128(3):691–701. doi: 10.1002/ijc.25367 PubMedCrossRefGoogle Scholar
  18. 18.
    Hoffman WH, Biade S, Zilfou JT et al (2002) Transcriptional repression of the anti-apoptotic survivin gene by wild type p53. J Biol Chem 277:3247–3257. doi: 10.1074/jbc.M106643200 PubMedCrossRefGoogle Scholar
  19. 19.
    Zhang T, Otevrel T, Gao Z et al (2001) Evidence that APC regulates survivin expression: a possible mechanism contributing to the stem cell origin of colon cancer. Cancer Res 61:8664–8667PubMedGoogle Scholar
  20. 20.
    Zhu P, Martin E, Mengwasser J et al (2004) Induction of HDAC2 expression upon loss of APC in colorectal tumorigenesis. Cancer Cell 5:455–463. doi: 10.1016/S1535-6108(04)00114X PubMedCrossRefGoogle Scholar
  21. 21.
    Zimmermann S, Kiefer F, Prudenziati M et al (2007) Reduced body size and decreased intestinal tumor rates in HDAC2-mutant mice. Cancer Res 67:9047–9054. doi: 10.1158/0008-5472.CAN-07-0312 PubMedCrossRefGoogle Scholar
  22. 22.
    Ravdin PM, Cronin KA, Howlader N et al (2007) The decrease in breast-cancer incidence in 2003 in the United States. N Engl J Med 356:1670–1674. doi: 10.1056/NEJMsr070105 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Lei Zhang
    • 1
    • 2
  • Guiying Wang
    • 1
  • Lin Wang
    • 2
  • Chenlin Song
    • 1
  • Ye Leng
    • 1
  • Xinhua Wang
    • 2
  • Jiuhong Kang
    • 1
  1. 1.Clinical and Translational Research Center at Shanghai First Maternity & Infant Health Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and TechnologyTongji UniversityShanghaiChina
  2. 2.Dongfang HospitalTongji UniversityShanghaiPeople’s Republic of China

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