Loss of PTEN Accelerates NKX3.1 Degradation to Promote Prostate Cancer Progression
MetadataShow full item record
PublisherAMER ASSOC CANCER RESEARCH
CitationBowen, 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.
Rights© 2019 American Association for Cancer Research.
Collection InformationThis 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 firstname.lastname@example.org.
AbstractNKX3.1 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.
Note12 month embargo; published online: 18 June 2019
VersionFinal accepted manuscript
SponsorsFalconwood Foundation; NCI [P01 CA154293]; CCSG [P30 CA013696-36]
- The Tumor Suppressor NKX3.1 Is Targeted for Degradation by DYRK1B Kinase.
- Authors: Song LN, Silva J, Koller A, Rosenthal A, Chen EI, Gelmann EP
- Issue date: 2015 May
- Loss of Nkx3.1 leads to the activation of discrete downstream target genes during prostate tumorigenesis.
- Authors: Song H, Zhang B, Watson MA, Humphrey PA, Lim H, Milbrandt J
- Issue date: 2009 Sep 17
- Id4 deficiency attenuates prostate development and promotes PIN-like lesions by regulating androgen receptor activity and expression of NKX3.1 and PTEN.
- Authors: Sharma P, Knowell AE, Chinaranagari S, Komaragiri S, Nagappan P, Patel D, Havrda MC, Chaudhary J
- Issue date: 2013 Jun 21
- CRISPR/Cas9-Mediated Point Mutation in <i>Nkx3.1</i> Prolongs Protein Half-Life and Reverses Effects <i>Nkx3.1</i> Allelic Loss.
- Authors: Bowen C, Shibata M, Zhang H, Bergren SK, Shen MM, Gelmann EP
- Issue date: 2020 Nov 1
- NKX3.1 stabilizes p53, inhibits AKT activation, and blocks prostate cancer initiation caused by PTEN loss.
- Authors: Lei Q, Jiao J, Xin L, Chang CJ, Wang S, Gao J, Gleave ME, Witte ON, Liu X, Wu H
- Issue date: 2006 May