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.