Distinct mechanisms for TMPRSS2 expression explain organ-specific inhibition of SARS-CoV-2 infection by enzalutamide [ChIP-Seq]

Description: Summary from the GEO: "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."

Overall design from the GEO: "AR-ChIP-seq was performed in AR-positive lung cancer cells A549, H2126 and H1437 and prostate cancer cells LNCaP"

Subject of Study

Homo sapiens

Subject(s)

COVID-19

Lung Neoplasms

Oncogene Proteins, Fusion

Prostatic Neoplasms

OncoTree Cancer Type(s)

Prostate

Access via GEO
BIGWIG and NARROWPEAK files of genome binding/occupancy profiling by high throughput sequencing
Accession #: GSE163623

Access via SRA
ChIP Sequencing data of 5 samples
Accession #: SRP298732

Access via BioProject
Additional information about the overall inititative.
Accession #: PRJNA686969
Access Restrictions: Free to All
Access Instructions: The NCBI Gene Expression Omnibus, SRA and BioProject databases provide open access to these files. SRA and/or tar files can be downloaded directly from the site or viewed in the NCBI SRA Run Selector (link at bottom of page).
Associated Publications: Li F, Han M, Dai P, et al. Distinct mechanisms for TMPRSS2 expression explain organ-specific inhibition of SARS-CoV-2 infection by enzalutamide. Nature Communications. 2021; 12:866.
Data Type: Genomic
Equipment Used: Illumina NovaSeq 6000
Software Used: SRA Toolkit
The NCBI SRA Toolkit enables reading ("dumping") of sequencing files from the SRA database and writing ("loading") files into the .sra format.
Dataset Format(s): SRA, TAR, BIGWIG, NARROWPEAK
Data Tool(s): ChIP Seq
Dataset Size: 736.5 Mb (TAR of BW, NARROWPEAK), 18.2 Gb (SRA)

Data Catalog Record Updated: 2023-12-07