Faculty Collaboration Database

Loss of PTEN Accelerates NKX3.1 Degradation to Promote Prostate Cancer Progression. Cancer Res 2019 Aug 15;79(16):4124-4134

Date

06/20/2019

Pubmed ID

31213464

Pubmed Central ID

PMC6753942

DOI

10.1158/0008-5472.CAN-18-4110

Scopus ID

2-s2.0-85070602387 (requires institutional sign-in at Scopus site)   31 Citations

Abstract

NKX3.1 is the most commonly deleted gene in prostate cancer and a gatekeeper suppressor. NKX3.1 is a growth suppressor, mediator of apoptosis, inducer of antioxidants, and enhancer of DNA repair. PTEN is a ubiquitous tumor suppressor that is often decreased in prostate cancer during tumor progression. Steady-state turnover of NKX3.1 is mediated by DYRK1B phosphorylation at NKX3.1 serine 185 that leads to polyubiquitination and proteasomal degradation. In this study, we show PTEN is an NKX3.1 phosphatase that protects NKX3.1 from degradation. PTEN specifically opposed phosphorylation at NKX3.1(S185) and prolonged NKX3.1 half-life. PTEN and NKX3.1 interacted primarily in the nucleus as loss of PTEN nuclear localization abrogated its ability to bind to and protect NKX3.1 from degradation. The effect of PTEN on NKX3.1 was mediated via rapid enzyme-substrate interaction. An effect of PTEN on Nkx3.1 gene transcription was seen in vitro, but not in vivo. In gene-targeted mice, Nkx3.1 expression significantly diminished shortly after loss of Pten expression in the prostate. Nkx3.1 loss primarily increased prostate epithelial cell proliferation in vivo. In these mice, Nkx3.1 mRNA was not affected by Pten expression. Thus, the prostate cancer suppressors PTEN and NKX3.1 interact and loss of PTEN is responsible, at least in part, for progressive loss of NKX3.1 that occurs during tumor progression. SIGNIFICANCE: PTEN functions as a phosphatase of NKX3.1, a gatekeeper suppressor of prostate cancer.

Author List

Bowen C, Ostrowski MC, Leone G, Gelmann EP

Author

Gustavo Leone PhD Sr Associate Dean, Director, Professor in the Pathology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Cell Line, Tumor
Gene Expression Regulation, Neoplastic
Homeodomain Proteins
Humans
Male
Mice, Knockout
PTEN Phosphohydrolase
Phosphorylation
Prostate
Prostatic Neoplasms
Protein-Tyrosine Kinases
Transcription Factors