Activation of silenced tumor suppressor genes in prostate cancer cells by a novel energy restriction-mimetic agent

Hsiang Yu Lin, Yi Chiu Kuo, Yu I. Weng, I. Lu Lai, Tim H.M. Huang, Shuan Pei Lin, Dau Ming Niu, Ching Shih Chen

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Background. Targeting tumor metabolism by energy restriction-mimetic agents (ERMAs) has emerged as a strategy for cancer therapy/prevention. Evidence suggests a mechanistic link between ERMA-mediated antitumor effects and epigenetic gene regulation. Methods. Microarray analysis showed that a novel thiazolidinedione-derived ERMA, CG-12, and glucose deprivation could suppress DNA methyltransferase (DNMT)1 expression and reactivate DNA methylation-silenced tumor suppressor genes in LNCaP prostate cancer cells. Thus, we investigated the effects of a potent CG-12 derivative, CG-5, vis-À-vis 2-deoxyglucose, glucose deprivation and/or 5-aza-deoxycytidine, on DNMT isoform expression (Western blotting, RT-PCR), DNMT1 transcriptional activation (luciferase reporter assay), and expression of genes frequently hypermethylated in prostate cancer (quantitative real-time PCR). Promoter methylation was assessed by pyrosequencing analysis. SiRNA-mediated knockdown and ectopic expression of DNMT1 were used to validate DNMT1 as a target of CG-5. Results. CG-5 and glucose deprivation upregulated the expression of DNA methylation-silenced tumor suppressor genes, including GADD45a, GADD45b, IGFBP3, LAMB3, BASP1, GPX3, and GSTP1, but also downregulated methylated tumor/invasion-promoting genes, including CD44, S100A4, and TACSTD2. In contrast, 5-aza-deoxycytidine induced global reactivation of these genes. CG-5 mediated these epigenetic effects by transcriptional repression of DNMT1, which was associated with reduced expression of Sp1 and E2F1. SiRNA-mediated knockdown and ectopic expression of DNMT1 corroborated DNMT1's role in the modulation of gene expression by CG-5. Pyrosequencing revealed differential effects of CG-5 versus 5-aza-deoxycytidine on promoter methylation in these genes. Conclusions. These findings reveal a previously uncharacterized epigenetic effect of ERMAs on DNA methylation-silenced tumor suppressor genes, which may foster novel strategies for prostate cancer therapy.

Original languageEnglish (US)
Pages (from-to)1767-1778
Number of pages12
JournalProstate
Volume72
Issue number16
DOIs
StatePublished - Dec 1 2012
Externally publishedYes

Keywords

  • DNA methyltransferases
  • energy restriction
  • energy restriction-mimetic agent
  • epigenetics
  • prostate cancer

ASJC Scopus subject areas

  • Oncology
  • Urology

Fingerprint Dive into the research topics of 'Activation of silenced tumor suppressor genes in prostate cancer cells by a novel energy restriction-mimetic agent'. Together they form a unique fingerprint.

  • Cite this

    Lin, H. Y., Kuo, Y. C., Weng, Y. I., Lai, I. L., Huang, T. H. M., Lin, S. P., Niu, D. M., & Chen, C. S. (2012). Activation of silenced tumor suppressor genes in prostate cancer cells by a novel energy restriction-mimetic agent. Prostate, 72(16), 1767-1778. https://doi.org/10.1002/pros.22530