title: Ligand-dependent corepressor acts as a novel androgen receptor corepressor, inhibits prostate cancer growth, and is functionally inactivated by the Src protein kinase.
abstract: The activated androgen receptor (AR) promotes prostate cancer (PCa) growth. AR antagonists repress the AR by recruitment of corepressors. Not much is known about the inactivation of AR by corepressors in the presence of agonists (androgens). Here we show that the corepressor LCoR acts as an androgen-dependent corepressor that represses human PCa growth in vivo. In line with this, progressive decrease of ligand-dependent corepressor expression was observed in the PCa TRAMP mouse model with increasing age. LCoR interacts with AR and is recruited to chromatin in an androgen-induced manner. Unexpectedly, the LXXLL motif of LCoR is dispensable for interaction with the AR. Rather, the data indicate that LCoR interacts with the AR DNA binding domain on DNA. Interestingly, the interaction of LCoR with AR is inhibited by signaling pathways that are associated with androgen-independent PCa. Here we also show that the Src kinase inactivates the corepressive function of LCoR. Interfering with endogenous Src function by a dominant negative Src mutant, the growth inhibitory activity of LCoR is enhanced in vivo in a xenograft mouse model system. Thus, our studies indicate a role of LCoR as an AR corepressor and a tumor suppressor. Further, the decreased expression or inactivation of LCoR is as an important step toward PCa carcinogenesis in vivo.
authors.affiliation: Department of Dermatology, University of Wisconsin, Madison, Wisconsin, USA.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Asim
authors.forename: Bilal Bin
authors.initials: BB
authors.lastname: Hafeez
authors.forename: Imtiaz Ahmad
authors.initials: IA
authors.lastname: Siddiqui
authors.forename: Claudia
authors.initials: C
authors.lastname: Gerlach
authors.forename: Michaela
authors.initials: M
authors.lastname: Patz
authors.forename: Hasan
authors.initials: H
authors.lastname: Mukhtar
authors.forename: Aria
authors.initials: A
authors.lastname: Baniahmad
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D004273:DNA, Neoplasm; C472166:LCOR protein, human; D009363:Neoplasm Proteins; D011944:Receptors, Androgen; D012097:Repressor Proteins; D019061:src-Family Kinases