Prostate-specific loss of UXT promotes cancer progression.

Autor:	Wang Y; Department of Urology, New York University School of Medicine, New York 10016, NY, USA.; Department of Microbiology, New York University School of Medicine, New York 10016, NY, USA., Schafler ED; Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York 10016, NY, USA., Thomas PA; Department of Urology, New York University School of Medicine, New York 10016, NY, USA.; Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York 10016, NY, USA., Ha S; Department of Urology, New York University School of Medicine, New York 10016, NY, USA., David G; Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York 10016, NY, USA., Adney E; Institute for Systems Genetics, New York University School of Medicine, New York 10016, NY, USA.; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore 21205, MD, USA., Garabedian MJ; Department of Urology, New York University School of Medicine, New York 10016, NY, USA.; Department of Microbiology, New York University School of Medicine, New York 10016, NY, USA., Lee P; Department of Urology, New York University School of Medicine, New York 10016, NY, USA.; Department of Pathology, New York Harbor Healthcare System, New York 10010, NY, USA., Logan SK; Department of Urology, New York University School of Medicine, New York 10016, NY, USA.; Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York 10016, NY, USA.
Jazyk:	angličtina
Zdroj:	Oncotarget [Oncotarget] 2019 Jan 22; Vol. 10 (7), pp. 707-716. Date of Electronic Publication: 2019 Jan 22 (Print Publication: 2019).
DOI:	10.18632/oncotarget.26573
Abstrakt:	Ubiquitously-expressed, prefoldin-like chaperone (UXT) also called Androgen Receptor Trapped clone-27 (ART-27) is widely expressed in human tissues. Our previous studies showed that UXT regulates transcription repression including androgen receptor (AR) signaling in prostate cancer. Here we analyzed a tissue microarray consisting of normal prostate, benign prostatic hyperplasia, high grade prostatic intraepithelial neoplasia (HGPIN) and primary prostate cancer cases for UXT protein expression. We found that HGPIN and malignant tumors have significantly decreased UXT expression compared to the normal prostate. Loss of UXT expression in primary prostate cancer is positively associated with high Gleason grade and poor relapse-free survival. We engineered prostate-specific Uxt KO mice that developed a hyperplastic phenotype with apparent prostate secretion fluid blockage as well as PIN by 4-6 months. Doubly mutant Uxt KO / Pten KO mice developed a more aggressive PIN phenotype. UXT depletion in prostate cancer cells also increased retroelements expression, including LINE-1 and Alu. Consistent with this finding Uxt KO mice have increased LINE-1 protein levels in the prostate compared to control mice. In addition, cancer cells with UXT depletion have increased retrotransposition activity and accumulated DNA damage. Our findings demonstrate that loss of UXT is an early event during prostate cancer progression, which may contribute to genome instability. Competing Interests: CONFLICTS OF INTEREST Authors declare no conflicts of interest.
Databáze:	MEDLINE
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