Wang Yu, Schafler Eric D, Thomas Phillip A, Ha Susan, David Gregory, Adney Emily, Garabedian Michael J, Lee Peng, Logan Susan K
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.
Oncotarget. 2019 Jan 22;10(7):707-716. doi: 10.18632/oncotarget.26573.
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 mice that developed a hyperplastic phenotype with apparent prostate secretion fluid blockage as well as PIN by 4-6 months. Doubly mutant / 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 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.
泛素表达的类预折叠蛋白伴侣（UXT）也称为雄激素受体捕获克隆27（ART-27），在人体组织中广泛表达。我们之前的研究表明，UXT调节转录抑制，包括前列腺癌中的雄激素受体（AR）信号传导。在此，我们分析了一个组织芯片，其包含正常前列腺、良性前列腺增生、高级别前列腺上皮内瘤变（HGPIN）和原发性前列腺癌病例，用于检测UXT蛋白表达。我们发现，与正常前列腺相比，HGPIN和恶性肿瘤中的UXT表达显著降低。原发性前列腺癌中UXT表达的缺失与高Gleason分级和无复发生存期差呈正相关。我们构建了前列腺特异性小鼠，这些小鼠在4至6个月时出现增生表型，伴有明显的前列腺分泌液阻塞以及前列腺上皮内瘤变（PIN）。双突变/小鼠表现出更具侵袭性的PIN表型。前列腺癌细胞中UXT的缺失也增加了逆转录元件的表达，包括LINE-1和Alu。与这一发现一致，与对照小鼠相比，小鼠前列腺中的LINE-1蛋白水平增加。此外，UXT缺失的癌细胞具有增加的逆转录转座活性并积累了DNA损伤。我们的研究结果表明，UXT的缺失是前列腺癌进展过程中的早期事件，这可能导致基因组不稳定。
