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DNA damage-binding complex recruits HDAC1 to repress Bcl-2 transcription in human ovarian cancer cells

Ran Zhao1, Chunhua Han, Eric Eisenhauer

  • 1Department of Radiology, The Ohio State University, Room 1014 BRT, 460 W. 12th Avenue, Columbus, OH 43210. qi-en.wang@osumc.edu.

Molecular Cancer Research : MCR
|November 20, 2013
PubMed
Abstract

Insights

DNA damage-binding protein complex subunit 2 (DDB2) represses Bcl-2 transcription with DDB1, sensitizing ovarian cancer cells to cisplatin. This mechanism involves DDB2 binding the Bcl-2 promoter and recruiting HDAC1 to reduce acetylation, offering a potential cancer therapy strategy.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Epigenetics

Background:

  • Elevated Bcl-2 expression contributes to cisplatin resistance in multiple cancers.
  • DNA damage-binding protein complex subunit 2 (DDB2) sensitizes ovarian cancer cells to cisplatin via Bcl-2 downregulation.
  • The precise molecular mechanism of DDB2's action on Bcl-2 remains unclear.

Purpose of the Study:

  • To elucidate the molecular mechanism by which DDB2 represses Bcl-2 transcription.
  • To investigate the role of DDB1 and histone deacetylase 1 (HDAC1) in DDB2-mediated Bcl-2 regulation.
  • To determine the functional significance of DDB2-mediated repression of Bcl-2 in cisplatin-induced apoptosis.

Main Methods:

  • Quantitative ChIP and EMSA assays to assess DDB2 binding to the Bcl-2 promoter.
  • Analysis of histone acetylation (H3K9,14) and HDAC1 enrichment at Bcl-2 regulatory regions.
  • Coimmunoprecipitation and in vitro binding assays to detect protein-protein interactions.
  • Functional studies using wild-type and mutated DDB2 in cisplatin-treated ovarian cancer cells.

Main Results:

  • DDB2 functions as a transcriptional repressor of Bcl-2 in conjunction with DDB1.
  • DDB2 directly binds to a specific element within the Bcl-2 P1 promoter.
  • DDB2 overexpression reduces histone H3K9,14 acetylation and enriches HDAC1 at Bcl-2 promoter/enhancer regions.
  • DDB1 interacts with HDAC1, and HDAC1 downregulation increases Bcl-2 promoter activity.
  • Mutated DDB2, unable to repress Bcl-2, results in compromised cisplatin-induced apoptosis.

Conclusions:

  • DDB1 and DDB2 cooperate to repress Bcl-2 transcription by recruiting HDAC1 to deacetylate histone H3K9,14, suppressing Bcl-2 expression.
  • This mechanism highlights DDB2's role in overcoming cisplatin resistance.
  • Enhancing DDB complex expression presents a potential molecular strategy for cancer therapy.

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