title: Inhibition of p53 expression modifies the specificity of chromatin binding by the androgen receptor.
abstract: The androgen receptor (AR) is known to play a critical role in prostate cancer (PC). p53 likely also plays a role given that p53 mutations are commonly found in advanced PC, and loss of wild-type protein function contributes to the phenotype of castration-resistant prostate cancer (CRPC). Nevertheless, the extent of the contribution of p53 dysfunction to PC remains unclear. Here we analyze the effects of p53 inhibition in PC cells and show that it has significant consequences for both the interaction between AR, and chromatin and the proliferative capacity of these cells. Inhibition of p53 expression enabled LNCaP cells to proliferate independently of androgens. Moreover, it modified the genome-wide binding pattern of AR. ChIP-sequnce analyis (ChIP-seq) revealed that fewer AR-binding sites were present in the context of p53 inhibition, suggesting that wild-type p53 is required for stable binding of AR to certain chromatin regions. Further analysis revealed that a lower AR occupancy was accompanied by a reduction in FoxA1 binding at regulatory regions of AR-dependent genes. Our study also identifies a pool of genes that may be transcriptionally regulated by AR only in the absence of p53, and that may contribute to the CRPC phenotype. Overall, our results point to p53 playing an important role in regulating AR activity across the genome.
authors.affiliation: Department of Pathology, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA. natalya-guseva@uiowa.edu
authors.forename: Natalya V
authors.initials: NV
authors.lastname: Guseva
authors.forename: Oskar W
authors.initials: OW
authors.lastname: Rokhlin
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Bair
authors.forename: Rebecca B
authors.initials: RB
authors.lastname: Glover
authors.forename: Michael B
authors.initials: MB
authors.lastname: Cohen
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002843:Chromatin / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000378:metabolism; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D002843:Chromatin; C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D011944:Receptors, Androgen; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53