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Assays for Validating Histone Acetyltransferase Inhibitors
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Assays for Validating Histone Acetyltransferase Inhibitors

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MS-275, a histone deacetylase inhibitor, selectively induces transforming growth factor beta type II receptor

B I Lee1, S H Park, J W Kim

  • 1Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, Maryland 20892, USA.

Cancer Research
|February 28, 2001
PubMed

Insights

Histone deacetylase inhibitor MS-275 combats human breast cancer by reactivating the transforming growth factor-beta type II receptor (TbetaRII) gene. This epigenetic modification restores TGF-beta signaling, potentially mediating the drug's antitumor effects.

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • Transcriptional repression of the transforming growth factor-beta type II receptor (TbetaRII) gene is crucial for inactivating TGF-beta signaling in human cancers.
  • Histone acetylation and deacetylation are key regulators of gene transcription.

Purpose of the Study:

  • To investigate the effects of MS-275, a histone deacetylase inhibitor, on human breast cancer cell lines.
  • To determine if MS-275 can restore TbetaRII gene expression and TGF-beta responsiveness.

Main Methods:

  • Treatment of human breast cancer cell lines with MS-275.
  • Analysis of TbetaRII and TGF-beta type I receptor mRNA levels.
  • Assessment of histone H3 and H4 acetylation in chromatin and specific gene promoters.
  • Measurement of TGF-beta1-induced plasminogen activator inhibitor 1 expression.

Main Results:

  • MS-275 demonstrated antiproliferative activity against all tested breast cancer cell lines.
  • MS-275 induced TbetaRII mRNA expression, but not TGF-beta type I receptor mRNA.
  • MS-275 increased histone H3 and H4 acetylation in total chromatin and specifically at the TbetaRII promoter.
  • MS-275 enhanced TGF-beta1-induced plasminogen activator inhibitor 1 expression.

Conclusions:

  • MS-275 exhibits antitumor activity in human breast cancer cells.
  • The antiproliferative effects of MS-275 may be partly due to the induction of TbetaRII expression.
  • Restoration of TGF-beta signaling through TbetaRII re-expression is a potential mechanism for MS-275's efficacy.

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