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HDAC8 and STAT3 repress BMF gene activity in colon cancer cells

Y Kang1, H Nian2, P Rajendran3

  • 1Linus Pauling Institute, Oregon State University, Corvallis, OR, USA.

Cell Death & Disease
|October 17, 2014
PubMed

Insights

A novel seleno-α-keto acid triggers cancer cell death by reactivating the Bcl-2-modifying factor (Bmf) gene. This approach bypasses resistance mechanisms and offers a new strategy for developing targeted cancer therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Histone deacetylase (HDAC) inhibitors show promise as anticancer agents but can face resistance.
  • Resistance is often linked to anti-apoptotic Bcl-2 functions, specifically BH3-only protein silencing.
  • Reactivating BH3-only proteins offers a potential strategy to overcome HDAC inhibitor resistance.

Purpose of the Study:

  • To investigate a novel seleno-α-keto acid as an anticancer agent.
  • To explore its mechanism of action, focusing on histone acetylation and apoptosis induction.
  • To identify specific molecular targets and pathways involved in its therapeutic effect.

Main Methods:

  • Treatment of human colon cancer cells with a novel seleno-α-keto acid.
  • Assessment of global histone acetylation and apoptosis.
  • Profiling of survival factors and analysis of the Bcl-2-modifying factor (Bmf) gene promoter.
  • Investigation of transcription factors (STAT3, Sp3) and coactivators (p300) using inhibitors and RNA interference.

Main Results:

  • The seleno-α-keto acid induced global histone acetylation and p21-independent apoptosis in colon cancer cells.
  • Bcl-2-modifying factor (Bmf) was identified as a critical BH3-only member involved in the apoptotic response.
  • HDAC8 was found to directly repress BMF gene expression by interacting with STAT3/Sp3 and p300 on the BMF promoter.
  • The repressive function of HDAC8 on BMF could be dissociated from HDAC1, enabling Bmf-mediated apoptosis.

Conclusions:

  • This study identifies BMF as a direct target gene repressed by HDAC8.
  • HDAC8-selective inhibitors could be a promising therapeutic strategy for cancer, potentially uncoupling repression from HDAC1.
  • The findings offer new insights into overcoming resistance to HDAC inhibitors and developing targeted anticancer treatments.

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