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

UID: 10770

Author(s): Li, Fei

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: "ATAC-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
Access via GEO

BIGWIG and NARROWPEAK files of genome binding/occupancy profiling by high throughput sequencing
Accession #: GSE163624

Access via SRA

ATAC Sequencing of 4 samples
Accession #: SRP298734

Access via BioProject

Additional information about the overall inititative.
Accession #: PRJNA686970

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)
ATAC Seq
Dataset Size
471.9 MB (TAR of BW, NARROWPEAK), 27.7 Gb (SRA)
Data Catalog Record Updated
2023-12-07