Loss of PTEN Accelerates NKX3.1 Degradation to Promote Prostate Cancer Progression
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Final Accepted Manuscript
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AMER ASSOC CANCER RESEARCHCitation
Bowen, C., Ostrowski, M. C., Leone, G., & Gelmann, E. P. (2019). Loss of PTEN Accelerates NKX3. 1 Degradation to Promote Prostate Cancer Progression. Cancer Research, canres-4110.Journal
CANCER RESEARCHRights
© 2019 American Association for Cancer Research.Collection Information
This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.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.Note
12 month embargo; published online: 18 June 2019ISSN
0008-5472PubMed ID
31213464Version
Final accepted manuscriptSponsors
Falconwood Foundation; NCI [P01 CA154293]; CCSG [P30 CA013696-36]ae974a485f413a2113503eed53cd6c53
10.1158/0008-5472.CAN-18-4110
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