Prostate-specific loss of UXT promotes cancer progression
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Yu Wang1,2, Eric D. Schafler3, Phillip A. Thomas1,3, Susan Ha1, Gregory David3, Emily Adney4,6, Michael J. Garabedian1,2, Peng Lee1,5 and Susan K. Logan1,3
1Department of Urology, New York University School of Medicine, New York 10016, NY, USA
2Department of Microbiology, New York University School of Medicine, New York 10016, NY, USA
3Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York 10016, NY, USA
4Institute for Systems Genetics, New York University School of Medicine, New York 10016, NY, USA
5Department of Pathology, New York Harbor Healthcare System, New York 10010, NY, USA
6McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore 21205, MD, USA
Susan K. Logan, email: [email protected]
Keywords: UXT; retroelement; prostate cancer
Received: April 01, 2018 Accepted: October 06, 2018 Published: January 22, 2019
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 UxtKO mice that developed a hyperplastic phenotype with apparent prostate secretion fluid blockage as well as PIN by 4-6 months. Doubly mutant UxtKO/PtenKO 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 UxtKO 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.
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