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

Oncogene volume 38, pages 1121–1135 (2019)Cite this article

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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.

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Funding

This work was supported by NCI grant R15 CA179287-01A1 (IUA), NCI grant P30CA125123 (CC), CPRIT grant RP150648 (NLW, CC), and CPRIT grant RP170005 (CC).

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Authors and Affiliations

  1. Department of Chemistry and Biochemistry, Florida International University, Miami, FL, 33199, USA

    Manqi Zhang

  2. Department of Human and Molecular Genetics, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA

    Egla Suarez, Judy L. Vasquez & Irina U. Agoulnik

  3. Nova Southeastern University, Ft. Lauderdale, FL, USA

    Lubov Nathanson

  4. Center for Biostatistics, Houston Methodist Research Institute, Houston, TX, USA

    Leif E. Peterson

  5. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA

    Kimal Rajapakshe, Paul Basil, Nancy L. Weigel, Cristian Coarfa & Irina U. Agoulnik

  6. Biomolecular Science Institute, School of Integrated Science and Humanity, Florida International University, Miami, FL, 33199, USA

    Irina U. Agoulnik

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  1. Manqi Zhang
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Zhang, M., Suarez, E., Vasquez, J.L. et al. Inositol polyphosphate 4-phosphatase type II regulation of androgen receptor activity. Oncogene 38, 1121–1135 (2019). https://doi.org/10.1038/s41388-018-0498-3

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