Hypermethylation-mediated transcriptional repression of TMPRSS2 in androgen receptor-negative prostate cancer cells

Abstract

Prostate cancer is the most common type of cancer for men in the developed world. Androgen receptor (AR) is very important in prostate cancer progression. TMPRSS2 is an AR signaling downstream gene and closely related to prostate carcinogenesis. DNA methylation is a key mechanism to influence gene expression. Though previous reports have shown that AR signaling plays a critical role in the regulation of TMPRSS2 in prostate cancer, hardly any studies have examined whether the DNA methylation has been involved in the regulation of TMPRSS2. In the present study, we demonstrated that AR-negative prostate cancer (PCa) cells showed low expression levels and hypermethylation of TMPRSS2. In contrast, AR-positive PCa cells displayed high levels and hypomethylation of TMPRSS2. Treatment with the DNA methylation inhibitor 5-Aza-2'-deoxycytidine reversed the low expression levels of TMPRSS2 in the AR-negative PCa cells. Additionally, we found that the level of DNA methyltransferases 1 (DNMT1) was high in AR-negative PCa cells, in which hypermethylation of TMPRSS2 and low expression level of TMPRSS2 were observed. Collectively, these data suggest that the high level of DNMT1 might be the mechanism for the hypermethylation-mediated transcriptional repression of TMPRSS2 in AR-negative PCa cells.

DNA methylation and gene expression pattern of ACE2 and TMPRSS2 genes in saliva samples of patients with SARS-CoV-2 infection

“…ACE2 and TMPRSS2 expression is controlled by various regulatory mechanisms in the cell. [FitzGerald et al, 2008; Asselta et al, 2020; Zill et al, 2012; Chu et al, 2014]. In an Italian cohort, influence of genetic variants of ACE2 and TMPRSS2 on its expression was observed [FitzGerald et al, 2008; Asselta et al, 2020].…”

“…In an Italian cohort, influence of genetic variants of ACE2 and TMPRSS2 on its expression was observed [FitzGerald et al, 2008; Asselta et al, 2020]. These genes are also shown to be regulated by epigenetics [Zill et al, 2012; Chu et al, 2014]. It was predicted that there is differential methylation in ACE2 gene and that may be the cause of variability of its expression and it could be used to check the susceptibility of an individual to SARS-CoV-2 infection [Steyaert et al, 2020].…”

“…TMPRSS2 is an Androgen Receptor signalling downstream gene which is closely related to prostate carcinogenesis. DNA methylation is a key mechanism to influence gene expression in TMPRSS2 [Chu et al, 2014]. Protein expression studies showed that TMPRSS2 is highly expressed in lung epithelial cells when compared to other cells in lungs [Bertram et al, 2012].…”

Prostate Cancer: Epigenetic Alterations, Risk Factors, and Therapy

“…Aberrant hypermethylation of the Eph5A CpG promoter regions was observed in advanced PCa patients with a Gleason score of 8. Eph5A is one of the Eph family of receptors of tyrosine kinases that are implicated in several human malignancies including PCa and hepatocellular carcinoma [27, 28]. TMPRSS2, an AR signalling downstream gene, is a type II transmembrane protease abundantly expressed in the prostate gland that has been shown to induce tumorigenesis when altered.…”

“…DNMT1-induced hypermethylation at the promoter region of TMPRSS2 was observed in PCa cells. This was accompanied by a suppressed expression of AR and TMPRSS2 , which was restored through treatment with demethylating agent 5-Aza-2′-deoxycytidine [28]. Overexpression of ERα is directly proportional to PCa disease progression and promotes oncogenic events such as fusion of TMPRSS2 and estrogen-regulated gene ( ERG ) located on chromosome 21.…”