The pivotal role of TMPRSS2 in coronavirus disease 2019 and prostate cancer

The coronavirus disease 2019 (COVID-19) pandemic represents a public health emergency of international proportions, which is having catastrophic consequences throughout the world [1]. To date, around 6 million confirmed cases have been diagnosed worldwide and over 370,000 people perished because of COVID-19 [2]. The clinical disease called COVID-19 is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel betacoronavirus sharing 79% sequence identity with SARS-CoV, the agent which provoked the 2003 SARS outbreak [1]. Recent evidence suggested that SARS-CoV-2 uses the ACE2 receptor for cell entry, in synergy with the host’s TMPRSS2 [1]. More specifically, the viral S glycoprotein is cleaved by TMPRSS2, thus facilitating viral activation and representing one of the essential host factors for SARS-CoV-2 pathogenicity (Figure 1) [3]. This process is similar to viral activation and cell entry of other coronaviruses, including SARS-CoV, as well as influenza virus such as influenza H1N1 [4]. Despite several studies reported that in vitro activation of viral spikes could be mediated by other proteases such as TMPRSS4, TMPRSS11A, TMPRSS11D and TMPRSS11E1, TMPRSS2 activity is currently considered the sole crucial for cell entry and viral pathogenesis [3]. From the early days of coronavirus outbreak in China, significant differences in terms of severe cases and deaths have been reported between adult males and females (around 58 and 42%, respectively) [1]. Moreover, this pattern seems to be largely repeating itself, albeit with slightly different proportions, as indicated by recent epidemiological data across distinct continents and countries [4]. The international scientific community is investigating the reasons behind these gender differences, with biological and behavioral features (e.g., cigarette smoking) which have been called into question, including TMPRSS2 [3]. Interestingly, TMPRSS2 gene has a pivotal role also in prostate cancer development and progression. TMPRSS2 is expressed on the luminal side of the normal prostatic epithelium and it is increased in malignant prostatic tissue. In particular, the TMPRSS2:v-ets avian erythroblastosis virus E26 oncogene homolog (ERG) gene fusion is present in about 50% of prostate tumors in Caucasian men and is frequently an early event in prostate carcinogenesis [5,6]. TMPRS22 and ERG genes are located tandemly on chromosome 21q22 and expression of TMPRSS2 is androgenregulated and prostate-specific [7]. The fusion results from intrachromosomal deletion of ∼3-Mb of the interstitial region between the TMPRSS2 and ERG loci or from an insertion of the interstitial region causing a chromosomal rearrangement [7]. The role of this gene fusion is crucial in the development of prostate cancer because it leads to the activation of ERG transcription factor. In fact, in the presence of this gene fusion androgen-responsive elements within the TMPRSS2 promoter drive the overexpression of ERG. ERG is a member of the E-twenty-six family members (ETS), master transcription factors that have a key role in differentiation, apoptosis, cell proliferation and inflammation. TMPRSS2:ERG fusion can cause cancer progression by disrupting the androgen receptor (AR) lineage-specific differentiation program of the prostate and favoring EZH2-mediated cellular de-differentiation [8]. The gene fusion can produce a repression of the AR signaling, thus creating a selective pressure that leads to the development of recurrent tumors with AR amplification and resistance to hormone deprivation therapies. ERG can