Heterogeneous epigenetic regulation of TIMP3 in prostate cancer

Toshiaki Shinojima, Qiang Yu, Sharon K. Huang, Michelle Li, Ryuichi Mizuno, Edison T. Liu, Dave S.B. Hoon, Laurent Lessard

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Tissue inhibitor of metalloproteinase-3 (TIMP3) is a tumor suppressor gene frequently downregulated in prostate cancer. The mechanisms involved in TIMP3 transcriptional repression are not fully understood, but evidence suggests that promoter hypermethylation may not be the predominant epigenetic alteration in prostate cancer. To clarify this issue, we examined the contribution of both CpG site promoter methylation and histone modifications on TIMP3 downregulation. Using publicly available data sets, we confirmed that TIMP3 mRNA expression is decreased in prostate tumors relative to normal glands. Immunohistochemical analysis also showed decreased TIMP3 levels in high-grade primary tumors, but promoter hypermethylation was only detected in 6 of 28 (21%) high-grade specimens. Similarly, in prostate cancer cells, TIMP3 hypermethylation was only observed in DU145 cells. Treatment of DU145 cells with 5-aza-2'-deoxycytidine (5-Aza-CdR) restored TIMP3 expression, and this was significantly amplified by co-treating the cells with the HDAC inhibitor trichostatin A (TSA). Alternatively, in cells that did not exhibit aberrant TIMP3 methylation (LNCaP and PC 3), TIMP3 expression could be upregulated by the combination of histone methylation inhibitor 3-Deazaneplanocin A (DZNep) and TSA. This reversal of transcriptional repression was associated with decreased H3K27me3 and increased H3K9ac histone marks at the TIMP3 promoter, as demonstrated by chromatin immunoprecipitation. Collectively, these results indicate that histone modifications can contribute to TIMP3 repression in the absence of promoter hypermethylation, and suggest that the combination of histone modifying agents could restore TIMP3 expression in prostate tumors harboring aberrant histone modifications at the TIMP3 promoter.

Original languageEnglish
Pages (from-to)1279-1289
Number of pages11
JournalEpigenetics
Volume7
Issue number11
DOIs
Publication statusPublished - 2012 Nov

Keywords

  • DNA methylation
  • Epigenetic drugs
  • Histone modifications
  • Prostate cancer
  • TIMP3

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

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  • Cite this

    Shinojima, T., Yu, Q., Huang, S. K., Li, M., Mizuno, R., Liu, E. T., Hoon, D. S. B., & Lessard, L. (2012). Heterogeneous epigenetic regulation of TIMP3 in prostate cancer. Epigenetics, 7(11), 1279-1289. https://doi.org/10.4161/epi.22333