title: BRG1, the ATPase subunit of SWI/SNF chromatin remodeling complex, interacts with HDAC2 to modulate telomerase expression in human cancer cells.
abstract: Telomerase is often upregulated during initiation and/or progression of human tumors, suggesting that repression of telomerase might inhibit cancer growth or progression. Here, we report that BRG1, the ATPase subunit of the SWI/SNF chromatin remodeling complex, is a general suppressor of hTERT transcription in human cancer cells. While overexpression of BRG1 inhibits hTERT transcription, depletion of BRG1 stimulates transcription of hTERT, leading to higher telomerase activity and longer telomeres. Chromatin-immunoprecipitation assays revealed that BRG1 binds to the transcription start site (TSS) of the hTERT promoter and forms a ternary complex with histone deacetylase 2 (HDAC2). BRG1 remodels chromatin structure to facilitate the action of HDAC2, leading to deacetylation of H3K9ac and H4ac at the TSS and suppression of hTERT transcription. On the other hand, β-catenin binds to the TSS and stimulates hTERT transcription. Thus, BRG1/HDAC2 and β-catenin constitute a manipulative apparatus at the TSS to play opposite but complementary roles in regulating hTERT expression. These results uncover a yin-yang mechanism in modulating hTERT transcription and provide explanation for limited transcription of hTERT in human cancer cells. BRG1/HDAC2 may have a potential as an anti-cancer therapeutic and/or for reactivating cellular proliferative capacity in the context of in vitro tissue engineering.
authors.affiliation: a The School of Life Sciences ; Tsinghua University ; Beijing , PR China.
authors.forename: Shu
authors.initials: S
authors.lastname: Wu
authors.forename: Yuanlong
authors.initials: Y
authors.lastname: Ge
authors.forename: Laiqiang
authors.initials: L
authors.lastname: Huang
authors.forename: Haiying
authors.initials: H
authors.lastname: Liu
authors.forename: Yong
authors.initials: Y
authors.lastname: Xue
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D000107:Acetylation; D000251:Adenosine Triphosphatases / Q000378:metabolism*; D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly; D004265:DNA Helicases / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D056464:Histone Deacetylase 2 / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008954:Models, Biological; D009687:Nuclear Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D021122:Protein Subunits / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D024363:Transcription Initiation Site; D014158:Transcription, Genetic; D051176:beta Catenin / Q000378:metabolism
chemical_list: D006657:Histones; D009687:Nuclear Proteins; D021122:Protein Subunits; D012333:RNA, Messenger; D014157:Transcription Factors; D051176:beta Catenin; D019098:Telomerase; C533423:HDAC2 protein, human; D056464:Histone Deacetylase 2; D000251:Adenosine Triphosphatases; C084108:SMARCA4 protein, human; D004265:DNA Helicases; D008239:Lysine
keywords: BRG1; HDACs; HDACs, histone deacetylase; SWI/SNF, SWItch/Sucrose NonFermentable; TSA, Trichostatin A; TSS, transcription start site; chromatin remodeling; telomerase; telomeres; β-catenin