Inositol polyphosphate 4-phosphatase type II regulation of androgen receptor activity

Manqi Zhang, Egla Suarez, Judy L. Vasquez, Lubov Nathanson, Leif E. Peterson, Kimal Rajapakshe, Paul Basil, Nancy L. Weigel, Cristian Coarfa, Irina U. Agoulnik

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Activation and transcriptional reprogramming of AR in advanced prostate cancer frequently coincides with the loss of two tumor suppressors, INPP4B and PTEN, which are highly expressed in human and mouse prostate epithelium. While regulation of AR signaling by PTEN has been described by multiple groups, it is not known whether the loss of INPP4B affects AR activity. Using prostate cancer cell lines, we showed that INPP4B regulates AR transcriptional activity and the oncogenic signaling pathways Akt and PKC. Analysis of gene expression in prostate cancer patient cohorts showed a positive correlation between INPP4B expression and both AR mRNA levels and AR transcriptional output. Using an Inpp4b −/− mouse model, we demonstrated that INPP4B suppresses Akt and PKC signaling pathways and modulates AR transcriptional activity in normal mouse prostate. Remarkably, PTEN protein levels and phosphorylation of S380 were the same in Inpp4b −/− and WT males, suggesting that the observed changes were due exclusively to the loss of INPP4B. Our data show that INPP4B modulates AR activity in normal prostate and its loss contributes to the AR-dependent transcriptional profile in prostate cancer.

Original languageEnglish (US)
Pages (from-to)1121-1135
Number of pages15
JournalOncogene
Volume38
Issue number7
DOIs
StatePublished - Feb 14 2019

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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