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

ABSTRACT: Elevated expression of the antiapoptotic factor Bcl-2 is believed to be one of the contributing factors to an increased relapse rate associated with multiple cisplatin-resistant cancers. DNA damage-binding protein complex subunit 2 (DDB2) has recently been revealed to play an important role in sensitizing human ovarian cancer cells to cisplatin-induced apoptosis through the downregulation of Bcl-2, but the underlying molecular mechanism remains poorly defined. Here, it is report that DDB2 functions as a transcriptional repressor for Bcl-2 in combination with DDB1. Quantitative ChIP and EMSA analysis revealed that DDB2 binds to a specific cis-acting element at the 5'-end of Bcl-2 P1 promoter. Overexpression of DDB2 resulted in marked losses of histone H3K9,14 acetylation along the Bcl-2 promoter and enhancer regions, concomitant with a local enrichment of HDAC1 to the Bcl-2 P1 core promoter in ovarian cancer cells. Coimmunoprecipitation and in vitro binding analyses identified a physical interaction between DDB1 and HDAC1, whereas downregulation of HDAC1 significantly enhanced Bcl-2 promoter activity. Finally, in comparison with wild-type DDB2, mutated DDB2, which is unable to repress Bcl-2 transcription, mediates a compromised apoptosis upon cisplatin treatment. Taken together, these data support a model wherein DDB1 and DDB2 cooperate to repress Bcl-2 transcription. DDB2 recognizes and binds to the Bcl-2 P1 promoter, and HDAC1 is recruited through the DDB1 subunit associated with DDB2 to deacetylate histone H3K9,14 across Bcl-2 regulatory regions, resulting in suppressed Bcl-2 transcription.Increasing the expression of DDB complex may provide a molecular strategy for cancer therapy.

SUBMITTER: Zhao R

PROVIDER: S-EPMC3962721 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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

Zhao Ran R Han Chunhua C Eisenhauer Eric E Kroger John J Zhao Weiqiang W Yu Jianhua J Selvendiran Karuppaiyah K Liu Xingluo X Wani Altaf A AA Wang Qi-En QE

Molecular cancer research : MCR 20131118 3

<h4>Unlabelled</h4>Elevated expression of the antiapoptotic factor Bcl-2 is believed to be one of the contributing factors to an increased relapse rate associated with multiple cisplatin-resistant cancers. DNA damage-binding protein complex subunit 2 (DDB2) has recently been revealed to play an important role in sensitizing human ovarian cancer cells to cisplatin-induced apoptosis through the downregulation of Bcl-2, but the underlying molecular mechanism remains poorly defined. Here, it is repo ...[more]

PMID: 24249678

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Project description:Cholesterol 7?-hydroxylase (CYP7A1) catalyzes the first and rate-limiting step in the classical pathway of bile acids synthesis in liver and is crucial for maintaining lipid homeostasis. Hepatocyte nuclear factor 4? (HNF4?) and ?1-fetoprotein transcription factor (FTF) are two major transcription factors driving CYP7A1 promoter activity in hepatocytes. Previous researches have shown that Prospero-related homeobox (Prox1) directly interacts with both HNF4? and FTF and potently co-represses CYP7A1 transcription and bile acid synthesis through unidentified mechanisms. In this work, mechanisms involved in Prox1-mediated co-repression were explored by identifying Prox1-associated proteins using immunoprecipitation followed by mass spectrometry (IP-MS) methodology. Multiple components of the epigenetically repressive lysine-specific demethylase 1 (LSD1)/nucleosome remodeling and histone deacetylase (NuRD) complex, most notably LSD1 and histone deacetylase 2 (HDAC2), were found to be associated with Prox1 and GST pulldown assay demonstrated that Prox1 directly interacts with LSD1. Sequential chromatin immunoprecipitation (ChIP) assays showed that Prox1 co-localizes with HNF4?, LSD1 and HDAC2 on CYP7A1 promoter in HepG2 cells. Furthermore, by using ChIP assay on HepG2 cells with endogenous Prox1 knocked down by RNA interference, Prox1 was shown to recruit LSD1 and HDAC2 onto CYP7A1 promoter and cause increased H3K4 demethylation. Finally, bile acids treatment of HepG2 cells, which significantly repressed CYP7A1 transcription, resulted in increased Prox1 and LSD1/NuRD complex occupancy on CYP7A1 promoter with a concurrent increase in H3K4 demethylation and H3/H4 deacetylation. These results showed that Prox1 interacts with LSD1 to recruit the repressive LSD1/NuRD complex to CYP7A1 promoter and co-represses transcription through epigenetic mechanisms. In addition, such Prox1-mediated epigenetic repression is involved in the physiologically essential negative feedback inhibition of CYP7A1 transcription by bile acids.

Dataset Information

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

Publications

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

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