Accession	GSE163623
Status	2020/12/22
Title	Distinct mechanisms for TMPRSS2 expression explain organ-specific inhibition of SARS-CoV-2 infection by enzalutamide [ChIP-Seq]
Organism	Homo sapiens
Experiment type	Genome binding/occupancy profiling by high throughput sequencing
Summary	The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly become a global public health threat due to the lack of effective drugs or vaccines against SARS-CoV-2. The efficacy of several repurposed drugs has been evaluated in clinical trials. Among these drugs, a second second-generation antiandrogen agent, enzalutamide, was proposed because it reduces the expression of transmembrane serine protease 2 (TMPRSS2), a key component mediating SARS-CoV-2-driven entry into host cells, in prostate cancer cells. However, definitive evidence for the therapeutic efficacy of enzalutamide in COVID-19 is lacking. Here, we evaluated the antiviral efficacy of enzalutamide in prostate cancer cells, lung cancer cells, human lung organoids and SARS-CoV-2-infected Ad-ACE2-transduced Tmprss2 knockout (Tmprss2-KO) and wild-type (WT) mice. TMPRSS2 knockout significantly inhibited SARS-CoV-2 infection in vivo. Enzalutamide effectively inhibited SARS-CoV-2 infection in human prostate cells, however, such antiviral efficacy of enzalutamide was lacking in human lung cells and organoids. Although Tmprss2 knockout effectively blocked SARS-CoV-2 infection in ACE2-transduced mice, Accordingly, enzalutamide showed no antiviral activity due to the AR-independent TMPRSS2 expression in mouse and human lung epithelial cells. Moreover, we observed distinct AR binding patterns between prostate cells and lung cells and a lack of direct binding of AR to TMPRSS2 in human lung cells. Thus, our findings do not support the postulated protective role of enzalutamide in treating COVID-19 through reducing TMPRSS2 expression in lung cells.
Samples	GSM ID Sample info Characteristics Description GSM4983055 AR_ChIP-seq in H1437 cell line:H1437; antibody:anti-AR antibody (Abcam, ab108341) - GSM4983056 AR_ChIP-seq in LNCaP cell line:LNCaP; antibody:anti-AR antibody (Abcam, ab108341) - GSM4983057 Input_mix for AR_ChIP-seq cell line:A549, H1437, H2126 and LNCaP; antibody:none - GSM4983053 AR_ChIP-seq in A549 cell line:A549; antibody:anti-AR antibody (Abcam, ab108341) - GSM4983054 AR_ChIP-seq in H2126 cell line:H2126; antibody:anti-AR antibody (Abcam, ab108341) -
Platform	GPL24676  : Illumina NovaSeq 6000 (Homo sapiens)
Literature	33558541
Download	Download Genome Binding/Occupancy Profiling Analysis Data