Androgen Receptor-Activated Enhancers Simultaneously Regulate Oncogene TMPRSS2 and lncRNA PRCAT38 in Prostate Cancer

Abstract

Prostate cancer is a common carcinoma in males, the development of which involves the androgen receptor (AR) as a key regulator. AR transactivation induces the high expression of androgen-regulated genes, including transmembrane protease serine 2 (TMPRSS2) and long noncoding RNA prostate cancer-associated transcript 38 (PRCAT38). PRCAT38 and TMPRSS2 are both located on chromosome 21, separated by a series of enhancers. PRCAT38 is a prostate-specific long noncoding RNA that is highly expressed in cancer tissue as compared to normal tissue. Here, we show chromatin looping by enhancers E1 and E2 with the promoters for PRCAT38 and TMPRSS2, indicating the co-regulation of PRCAT38 and TMPRSS2 by the same enhancers. The knockout of enhancer E1 or E2 simultaneously impaired the transcription of PRCAT38 and TMPRSS2 and inhibited cell growth and migration. Moreover, the loop formation and enhancer activity were mediated by AR/FOXA1 binding and the activity of acetyltransferase p300. Our findings demonstrate the utilization of shared enhancers in the joint regulation of two oncogenes in prostate cancer cells.

Gender differences in predictors of intensive care units admission among COVID-19 patients: The results of the SARS-RAS study of the Italian Society of Hypertension

“…A biological mechanism may explain the higher risk of men. The ability of androgens to regulate transmembrane protease serine 2 [23], i.e. the enzyme allowing the final interaction between ACE2 and SARS-CoV-2 and viral RNA entry into the cell, might take part in this mechanism [24].…”

Expression of SARS-CoV-2 receptor ACE2 and TMPRSS2 in human primary conjunctival and pterygium cell lines and in mouse cornea

“…ACE2 expression can also be noted in the epithelial cells of oral mucosa, vascular endothelial cells, type II pneumocytes, kidney, heart, and the central nervous system [24][25][26][27][28]. On the other hand, TMPRSS2 expression has been reported in primary human airway cells, type II pneumocytes and cancers [29,30].…”

A rational roadmap for SARS‐CoV‐2/COVID‐19 pharmacotherapeutic research and development: IUPHAR Review 29

“…TMPRSS2 is a single transmembrane domain protein with an extracellular serine protease domain, which appears to cleave substrates preferentially at basic residues (arg/lys), with a calcium-binding LDL receptor androgen-dependent amplification of ETS-regulated genes (Tomlins et al, 2005). TMPRSS2 expression is androgen-regulated (Chen et al, 2019;Lin et al, 1999). It is expressed highly in prostate cancer (Lin et al, 1999;Lucas et al, 2008) (for review, see Tanabe & List, 2017) and loss of TMPRSS2 in the prostate is associated with reduced metastatic potential (Lucas et al, 2014).…”