Prostate-specific loss of UXT promotes cancer progression

Abstract

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.

A comprehensive analysis of prefoldins and their implication in cancer

“…STAP1 is overexpressed in breast tumors and derived cell lines when compared to normal tissues and presents high protein levels in bladder, breast, ovary, and thyroid tumor tissues ( Zhao et al., 2005 ), suggesting that STAP1 has oncogenic activities. However, this increase was not detected in our study ( Figure 7 ) and recent data indicate that STAP1 expression was lost in high-grade prostatic intraepithelial neoplasia and prostate cancer samples when compared to normal tissues and in benign prostatic hyperplasia samples ( Wang et al., 2019 ). In line with the above results describing regulation of LINE-1 by URI, knocking out STAP1 in murine prostate cells leads to intraepithelial neoplasias in the tissue, probably due to the promotion of retrotransposition of LINE-1 elements, likely mediated by the interaction of this protein with KAP1 ( Wang et al., 2019 ).…”

Peculiar pathological, radiological and clinical features of skull‐base de‐differentiated chordomas. Results from a referral centre case–series and literature review

“…who demonstrated the presence of driver events in PI3K signalling genes in 17 of 104 (16%) sporadic chordomas, and speculated on the utility of targeting PI3K signalling in their treatment . Additionally, in another case we detected a mutation in TP53 and epigenetic aberrations in TERT, UXT and MAGEA11 , belonging to the larger family of cancer/testis antigens, whose expression is consistently detected in cancers of different histological origin and germinal cells . Conversely, TP53 mutation associated with p53 immunohistochemical overexpression has been reported in the sarcomatous component of four de‐differentiated chondrosarcomas and in de‐differentiated thyroid carcinomas …”

Regulation of epithelial cell differentiation by the Ubiquitous expressed transcript isoform 1 in ulcerative colitis

“…It consists of a small transcript (UXT‐V2) encoding 157 amino acids, and a large transcript (UXT‐V1) encoding 169 amino acids. UXT‐V2 is a nuclear protein that plays a role in cell proliferation or differentiation in several cancers, including colorectal cancer 20,45–47 . On the other hand, the cytoplasmic UXT‐V1 regulates TNFα‐induced apoptosis and innate antiviral signal transduction 22,43 .…”

“…UXT-V2 is a nuclear protein that plays a role in cell proliferation or differentiation in several cancers, including colorectal cancer. 20,[45][46][47] On the other hand, the cytoplasmic UXT-V1 regulates TNFα-induced apoptosis and innate antiviral signal transduction. 22,43 In this study, we detected high levels of UXT-V1 in mucosal biopsies from patients with UC.…”