title: PTP1B is an androgen receptor-regulated phosphatase that promotes the progression of prostate cancer.
abstract: The androgen receptor (AR) signaling axis plays a key role in the pathogenesis of prostate cancer. In this study, we found that the protein tyrosine phosphatase PTP1B, a well-established regulator of metabolic signaling, was induced after androgen stimulation of AR-expressing prostate cancer cells. PTP1B induction by androgen occurred at the mRNA and protein levels to increase PTP1B activity. High-resolution chromosome mapping revealed AR recruitment to two response elements within the first intron of the PTP1B encoding gene PTPN1, correlating with an AR-mediated increase in RNA polymerase II recruitment to the PTPN1 transcriptional start site. We found that PTPN1 and AR genes were coamplified in metastatic tumors and that PTPN1 amplification was associated with a subset of high-risk primary tumors. Functionally, PTP1B depletion delayed the growth of androgen-dependent human prostate tumors and impaired androgen-induced cell migration and invasion in vitro. However, PTP1B was also required for optimal cell migration of androgen-independent cells. Collectively, our results established the AR as a transcriptional regulator of PTPN1 transcription and implicated PTP1B in a tumor-promoting role in prostate cancer. Our findings support the preclinical testing of PTP1B inhibitors for prostate cancer treatment.
authors.affiliation: Goodman Cancer Research Centre, Montréal, Québec, Canada.
authors.forename: Laurent
authors.initials: L
authors.lastname: Lessard
authors.forename: David P
authors.initials: DP
authors.lastname: Labbé
authors.forename: Geneviève
authors.initials: G
authors.lastname: Deblois
authors.forename: Louis R
authors.initials: LR
authors.lastname: Bégin
authors.forename: Serge
authors.initials: S
authors.lastname: Hardy
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Mes-Masson
authors.forename: Fred
authors.initials: F
authors.lastname: Saad
authors.forename: Lloyd C
authors.initials: LC
authors.lastname: Trotman
authors.forename: Vincent
authors.initials: V
authors.lastname: Giguère
authors.forename: Michel L
authors.initials: ML
authors.lastname: Tremblay
mesh_terms: D000728:Androgens / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007438:Introns / Q000187:drug effects; D008297:Male; D051379:Mice; D016513:Mice, SCID; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000235:genetics*; D012319:RNA Polymerase II / Q000187:drug effects / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D024363:Transcription Initiation Site / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C410798:AR protein, human; D000728:Androgens; D011944:Receptors, Androgen; D012319:RNA Polymerase II; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1