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VPA inhibits renal cancer cell migration by targeting HDAC2 and down-regulating HIF-1α

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Abstract

Cell migration plays major roles in human renal 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. In this study, we found that VPA significantly inhibited cell migration but not proliferation of human renal cancer ACHN cells. Mechanistic studies found that VPA significantly inhibited the expression of HIF-1α. Knockdown of HIF-1α could obviously inhibited cell migration, while over-expression of HIF-1α markedly rescued the inhibition of VPA on cell migration. Further studies found that knockdown of HDAC2 completely mimicked the effects of VPA on HIF-1α and cell migration, and over-expression of HIF-1α could also rescue the effects of HDAC2 knockdown on cell migration. Collectively, these results indicated that the potential of specific inhibition of HDAC2 by small molecular chemicals may lead to future therapeutic agents in human renal cancer treatment.

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Abbreviations

RCC:

Renal cell carcinoma

ccRCC:

Clear cell renal cell carcinoma

VPA:

Valproic acid

PCR:

Polymerase chain reaction

786-O:

Cultivated cells of human renal cell cancer

ACHN:

Human kidney adenocarcinoma cell line

HDAC:

Histone deacetylase

HIF-1α:

Hypoxia-inducible factor-1 alpha

References

  1. Ji C, Li X, Zhang S et al (2011) Laparoscopic radiofrequency ablation of renal tumors: 32-month mean follow-up results of 106 patients. Urology 77(4):798–802

    Article  PubMed  Google Scholar 

  2. Iacovelli R, Lanoy E, Albiges L, Escudier B (2012) Tumour burden is an independent prognostic factor in metastatic renal cell carcinoma. BJU Int 110(11):1747–1753

    Article  PubMed  Google Scholar 

  3. Vanharanta S, Shu W, Brenet F et al (2013) Epigenetic expansion of VHL-HIF signal output drives multiorgan metastasis in renal cancer. Nat Med 19(1):50–56

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Giannini G, Cabri W, Fattorusso C, Rodriquez M (2012) Histone deacetylase inhibitors in the treatment of cancer: overview and perspectives. Future Med Chem 4(11):1439–1460

    Article  CAS  PubMed  Google Scholar 

  5. Dallavalle S, Pisano C, Zunino F et al (2012) Development and therapeutic impact of HDAC6-selective inhibitors. Biochem Pharmacol 84(6):756–765

    Article  CAS  PubMed  Google Scholar 

  6. Berendsen S, Broekman M, Seute T et al (2012) Valproic acid for the treatment of malignant gliomas: review of the preclinical rationale and published clinical results. Expert Opin Investig Drugs 21(9):1391–1415

    Article  CAS  PubMed  Google Scholar 

  7. Cotto M, Cabanillas F, Tirado M et al (2010) Epigenetic therapy of lymphoma using histone deacetylase inhibitors. Clin Transl Oncol 12(6):401–409

    Article  CAS  PubMed  Google Scholar 

  8. Sermeus A, Michiels C (2011) Reciprocal influence of the p53 and the hypoxic pathways. Cell Death Dis 2:e164

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Iqbal MM, Sohhan T, Mahmud SZ (2001) The effects of lithium, valproic acid, and carbamazepine during pregnancy and lactation. J Toxicol Clin Toxicol 39(4):381–392

    Article  CAS  PubMed  Google Scholar 

  10. Chen N, Chen LP, Zhang J et al (2012) Molecular characterization and expression analysis of three hypoxia-inducible factor alpha subunits, HIF-1α/2α/3α of the hypoxia-sensitive freshwater species, Chinese sucker. Gene 498(1):81–90

    Article  CAS  PubMed  Google Scholar 

  11. Schito L, Rey S, Tafani M et al (2012) Hypoxia-inducible factor 1-dependent expression of platelet-derived growth factor B promotes lymphatic metastasis of hypoxic breast cancer cells. Proc Natl Acad Sci USA 109(40):E2707–E2716

    Article  CAS  PubMed  Google Scholar 

  12. Richon VM (2010) Targeting histone deacetylases: development of vorinostat for the treatment of cancer. Epigenomics 2(3):457–465

    Article  CAS  PubMed  Google Scholar 

  13. Wang G, He J, Zhao J et al (2012) Class I and class II histone deacetylases are potential therapeutic targets for treating pancreatic cancer. PLoS One 7(12):e52095

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. McCormack E, Haaland I, Venås G et al (2012) Synergistic induction of p53 mediated apoptosis by valproic acid and nutlin-3 in acute myeloid leukemia. Leukemia 26(5):910–917

    Article  CAS  PubMed  Google Scholar 

  15. Mamlouk S, Wielockx B (2012) Hypoxia-inducible factors as key regulators of tumor inflammation. Int J Cancer. doi:10.1002/ijc.27901

  16. Edeline J, Rioux-Leclercq N (2008) Renal cell carcinoma and prognostic factors. Ann Pathol 28(5):374–380

    Article  PubMed  Google Scholar 

  17. Singh BN, Zhang G, Hwa YL et al (2010) Nonhistone protein acetylation as cancer therapy targets. Expert Rev Anticancer Ther 10(6):935–954

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Menegola E, Cappelletti G, Di Renzo F (2012) Epigenetic approaches and methods in developmental toxicology: role of HDAC inhibition in teratogenic events. Methods Mol Biol 889:373–383

    Article  CAS  PubMed  Google Scholar 

  19. Seuter S, Heikkinen S, Carlberg C (2013) Chromatin acetylation at transcription start sites and vitamin D receptor binding regions relates to effects of 1α,25-dihydroxyvitamin D3 and histone deacetylase inhibitors on gene expression. Nucleic Acids Res 41(1):110–124

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Verheul HM, Salumbides B, Van Erp K et al (2008) Combination strategy targeting the hypoxia inducible factor-1 alpha with mammalian target of rapamycin and histone deacetylase inhibitors. Clin Cancer Res 14(11):3589–3597

    Article  CAS  PubMed  Google Scholar 

  21. Geng H, Harvey CT, Pittsenbarger J et al (2011) HDAC4 protein regulates HIF1α protein lysine acetylation and cancer cell response to hypoxia. J Biol Chem 286(44):38095–38102

    Article  CAS  PubMed  Google Scholar 

  22. Xu Y, Li Y, Li H et al (2013) The accumulations of HIF-1α and HIF-2α by JNK and ERK are involved in biphasic effects induced by different levels of arsenite in human bronchial epithelial cells. Toxicol Appl Pharmacol 266(2):187–197

    Article  CAS  PubMed  Google Scholar 

  23. Qian DZ, Kachhap SK, Collis SJ et al (2006) Class II histone deacetylases are associated with VHL-independent regulation of hypoxia-inducible factor 1 alpha. Cancer Res 66(17):8814–8821

    Article  CAS  PubMed  Google Scholar 

  24. Kim MJ, Kim DE, Jeong IG et al (2012) HDAC inhibitors synergize antiproliferative effect of sorafenib in renal cell carcinoma cells. Anticancer Res 32(8):3161–3168

    CAS  PubMed  Google Scholar 

  25. Oddsson SJ, Hardarson S, Petursdottir V et al (2012) Synchronous pulmonary metastases from renal cell carcinoma—a whole nation study on prevalence and potential resectability. Scand J Surg 101(3):160–165

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was partially supported by grants from the National Natural Science Foundation of China (Nos. 81270831 and 81000311).

Conflict of interest

The authors declared no potential conflicts of interests with respect to the authorship and/or publication of this article.

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Authors and Affiliations

  1. Department of Urology, Shanghai Tenth People’s Hospital, Tongji University, No 301, Yanchang Mid-Road, Shanghai, 200072, China

    Feng-qiang Yang, Min Liu, Jianping Che, Wei Li, Wei Zhai, Guang-chun Wang & Jun-hua Zheng

  2. Department of Medicine, People’s Hospital in Xinyuan County, Xinjiang, 835800, China

    Feng-ping Yang

  3. Department of Biochemistry, FuDan University, Shanghai, 200032, China

    Xi Li

Authors
  1. Feng-qiang Yang
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  2. Min Liu
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  3. Feng-ping Yang
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  4. Jianping Che
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  5. Wei Li
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  6. Wei Zhai
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  7. Guang-chun Wang
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  8. Jun-hua Zheng
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  9. Xi Li
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Corresponding author

Correspondence to Jun-hua Zheng.

Additional information

Feng-qiang Yang, Min Liu and Feng-ping Yang have contributed equally to this work.

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Yang, Fq., Liu, M., Yang, Fp. et al. VPA inhibits renal cancer cell migration by targeting HDAC2 and down-regulating HIF-1α. Mol Biol Rep 41, 1511–1518 (2014). https://doi.org/10.1007/s11033-013-2996-2

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  • DOI: https://doi.org/10.1007/s11033-013-2996-2

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