title: Inactivation of ATM/ATR DNA damage checkpoint promotes androgen induced chromosomal instability in prostate epithelial cells.
abstract: The ATM/ATR DNA damage checkpoint functions in the maintenance of genetic stability and some missense variants of the ATM gene have been shown to confer a moderate increased risk of prostate cancer. However, whether inactivation of this checkpoint contributes directly to prostate specific cancer predisposition is still unknown. Here, we show that exposure of non-malignant prostate epithelial cells (HPr-1AR) to androgen led to activation of the ATM/ATR DNA damage response and induction of cellular senescence. Notably, knockdown of the ATM gene expression in HPr-1AR cells can promote androgen-induced TMPRSS2: ERG rearrangement, a prostate-specific chromosome translocation frequently found in prostate cancer cells. Intriguingly, unlike the non-malignant prostate epithelial cells, the ATM/ATR DNA damage checkpoint appears to be defective in prostate cancer cells, since androgen treatment only induced a partial activation of the DNA damage response. This mechanism appears to preserve androgen induced autophosphorylation of ATM and phosphorylation of H2AX, lesion processing and repair pathway yet restrain ATM/CHK1/CHK2 and p53 signaling pathway. Our findings demonstrate that ATM/ATR inactivation is a crucial step in promoting androgen-induced genomic instability and prostate carcinogenesis.
authors.affiliation: Department of Anatomy, The University of Hong Kong, Hong Kong, Special Administrative Region, China.
authors.forename: Yung-Tuen
authors.initials: YT
authors.lastname: Chiu
authors.forename: Ji
authors.initials: J
authors.lastname: Liu
authors.forename: Kaidun
authors.initials: K
authors.lastname: Tang
authors.forename: Yong-Chuan
authors.initials: YC
authors.lastname: Wong
authors.forename: Kum Kum
authors.initials: KK
authors.lastname: Khanna
authors.forename: Ming-Tat
authors.initials: MT
authors.lastname: Ling
mesh_terms: D000728:Androgens / Q000378:metabolism*; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002869:Chromosome Aberrations; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology*; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D006801:Humans; D008297:Male; D010766:Phosphorylation; D011467:Prostate / Q000378:metabolism*; D011471:Prostatic Neoplasms; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D014162:Transfection; D014178:Translocation, Genetic; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D020687:cdc25 Phosphatases / Q000378:metabolism
chemical_list: D000728:Androgens; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases