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. The identification of AR targets contributing to prostate tumorigenesis is thus critical for the development of more effective therapies. Herein, we examined whether the AR could regulate classical protein tyrosine phosphatases, a family of enzymes increasingly associated with oncogenic processes. We found that protein tyrosine phosphatase 1B (PTP1B), a well-established regulator of metabolic signaling, was induced after androgenic stimulation of AR-expressing prostate cancer cells. This effect was observed both at the mRNA and protein levels, and translated into increased PTP1B activity. High-resolution location analyses on tiled array covering chromosome 20q revealed the recruitment of the AR to two response elements located within the first intron of the PTP1B gene (PTPN1) and correlated with an increase in RNA polymerase II recruitment to the transcriptional start site of PTPN1. Analysis of copy number alterations revealed that both PTPN1 and AR genes are co-amplified in metastatic tumors, and that PTPN1 amplification is associated with a subset of high-risk primary tumors. At the functional level, PTP1B depletion significantly delayed LNCaP tumor growth in vivo, and impaired androgen-induced cell migration and invasion in vitro. Importantly, androgen-independent cells also required PTP1B for optimal cell migration. Collectively, our results establish the AR as a transcriptional regulator of PTPN1 transcription, and suggest that PTP1B plays a tumor-promoting role in prostate cancer. This has important implications for prostate cancer biology, and supports the pre-clinical testing of PTP1B inhibitors for the treatment of the disease.

Androgens alter T-cell immunity by inhibiting T-helper 1 differentiation

“…The effect of this has been shown recently in genome wide investigations where AR binding to DNA has been found to be associated with increased accessibility of the location and this could be how AR regulates Ptpn1 expression (29). Others have recently found that AR binds Ptpn1 in human prostate cancer cells, leading to Ptpn1 expression, although the binding was at a different location from the one we found (30). Although these observations implicate AR-mediated expression of Ptpn1, the question remains of why androgen regulates Ptpn1.…”

Proteomics of Microparticles with SILAC Quantification (PROMIS-Quan): A Novel Proteomic Method for Plasma Biomarker Quantification*

“…PTPN1 is frequently amplified in metastatic tumors and high risk primary tumors (47). Downregulation of PTPN1 correlates with better prognosis by delaying tumor occurrence, decreasing tumor growth rates and inhibiting cell migration (41). The predictive signature included two other proteins, LPP and SFXN3, which to our knowledge were not previously associated with prostate cancer.…”

“…7C). PTPN1 (protein tyrosine phosphatase nonreceptor type 1) was previously found to be correlated with prostate cancer progression (41); LPP (LIM protein) is involved in cell adhesion; SFXN3 (sideroflexin-3) was previously suggested as a serum tumor marker for oral squamous cell carcinoma (42). Altogether, using PROMISQuan we were able to capture significant differences between healthy and prostate cancer plasma microparticle proteins and identified candidate markers of the disease.…”

Protein tyrosine phosphatase PTP1B in cell adhesion and migration

“…PTP1B was shown to promote cell adhesion and motility in fibroblasts, 17,18 neurons, 3,19 platelets, 4 and several tumor cell lines. 12,[20][21][22] An inhibitory role has been described in fibroblasts, 23,24 primary aortic smooth muscle cells, 25 ovarian cancer cells, 26 and in glioblastoma multiforme tumor cell invasion in mice. 27 Remarkably, the positive role of PTP1B in cell motility was frequently associated with the stimulation of integrin-dependent signaling.…”