title: 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.
  
  
  CONCLUSIONS
  Increasing the expression of DDB complex may provide a molecular strategy for cancer therapy.
authors.affiliation: Department of Radiology, The Ohio State University, Room 1014 BRT, 460 W. 12th Avenue, Columbus, OH 43210. qi-en.wang@osumc.edu.
authors.forename: Ran
authors.initials: R
authors.lastname: Zhao
authors.forename: Chunhua
authors.initials: C
authors.lastname: Han
authors.forename: Eric
authors.initials: E
authors.lastname: Eisenhauer
authors.forename: John
authors.initials: J
authors.lastname: Kroger
authors.forename: Weiqiang
authors.initials: W
authors.lastname: Zhao
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yu
authors.forename: Karuppaiyah
authors.initials: K
authors.lastname: Selvendiran
authors.forename: Xingluo
authors.initials: X
authors.lastname: Liu
authors.forename: Altaf A
authors.initials: AA
authors.lastname: Wani
authors.forename: Qi-En
authors.initials: QE
authors.lastname: Wang
mesh_terms: D017209:Apoptosis / Q000502:physiology; D045744:Cell Line, Tumor; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D057809:HEK293 Cells; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: C091435:DDB1 protein, human; C117669:DDB2 protein, human; D004268:DNA-Binding Proteins; D006657:Histones; D019253:Proto-Oncogene Proteins c-bcl-2; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1