Targeting transcriptional regulation of SARS-CoV-2 entry factors ACE2 and TMPRSS2

Yuanyuan Qiao; Xiao-Ming Wang; Rahul Mannan; Sethuramasundaram Pitchiaya; Yuping Zhang; Jesse W Wotring; Lanbo Xiao; Dan R Robinson; Yi-Mi Wu; Jean Ching-Yi Tien; Xuhong Cao; Stephanie A Simko; Ingrid J Apel; Pushpinder Bawa; Steven Kregel; Sathiya P Narayanan; Gregory Raskind; Stephanie J Ellison; Abhijit Parolia; Sylvia Zelenka-Wang; Lisa McMurry; Fengyun Su; Rui Wang; Yunhui Cheng; Andrew D Delekta; Zejie Mei; Carla D Pretto; Shaomeng Wang; Rohit Mehra; Jonathan Z Sexton; Arul M Chinnaiyan

doi:10.1073/pnas.2021450118

Targeting transcriptional regulation of SARS-CoV-2 entry factors ACE2 and TMPRSS2

Proc Natl Acad Sci U S A. 2021 Jan 5;118(1):e2021450118. doi: 10.1073/pnas.2021450118. Epub 2020 Dec 28.

Authors

Yuanyuan Qiao^{1

2

3}, Xiao-Ming Wang^{1

2}, Rahul Mannan^{1

2}, Sethuramasundaram Pitchiaya^{1

2}, Yuping Zhang^{1

2}, Jesse W Wotring⁴, Lanbo Xiao^{1

2}, Dan R Robinson^{1

2}, Yi-Mi Wu^{1

2}, Jean Ching-Yi Tien^{1

2}, Xuhong Cao^{1

2

5}, Stephanie A Simko^{1

2}, Ingrid J Apel^{1

2}, Pushpinder Bawa^{1

2}, Steven Kregel^{1

2}, Sathiya P Narayanan¹, Gregory Raskind¹, Stephanie J Ellison¹, Abhijit Parolia^{1

2}, Sylvia Zelenka-Wang^{1

2}, Lisa McMurry^{1

2}, Fengyun Su¹, Rui Wang¹, Yunhui Cheng¹, Andrew D Delekta¹, Zejie Mei⁶, Carla D Pretto⁷, Shaomeng Wang^{1

3

4

7

8}, Rohit Mehra^{1

2

3}, Jonathan Z Sexton^{4

7

9

10}, Arul M Chinnaiyan^{1

2

3

5

11}

Affiliations

¹ Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109.
² Department of Pathology, University of Michigan, Ann Arbor, MI 48109.
³ Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109.
⁴ Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109.
⁵ Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI 48109.
⁶ State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, University of Chinese Academy of Sciences, Shanghai 200031, China.
⁷ Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109.
⁸ Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109.
⁹ Center for Drug Repurposing, University of Michigan, Ann Arbor, MI 48109.
¹⁰ Michigan Institute for Clinical and Health Research, University of Michigan, Ann Arbor, MI 48109.
¹¹ Department of Urology, University of Michigan, Ann Arbor, MI 48109.

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, employs two key host proteins to gain entry and replicate within cells, angiotensin-converting enzyme 2 (ACE2) and the cell surface transmembrane protease serine 2 (TMPRSS2). TMPRSS2 was first characterized as an androgen-regulated gene in the prostate. Supporting a role for sex hormones, males relative to females are disproportionately affected by COVID-19 in terms of mortality and morbidity. Several studies, including one employing a large epidemiological cohort, suggested that blocking androgen signaling is protective against COVID-19. Here, we demonstrate that androgens regulate the expression of ACE2, TMPRSS2, and androgen receptor (AR) in subsets of lung epithelial cells. AR levels are markedly elevated in males relative to females greater than 70 y of age. In males greater than 70 y old, smoking was associated with elevated levels of AR and ACE2 in lung epithelial cells. Transcriptional repression of the AR enhanceosome with AR or bromodomain and extraterminal domain (BET) antagonists inhibited SARS-CoV-2 infection in vitro. Taken together, these studies support further investigation of transcriptional inhibition of critical host factors in the treatment or prevention of COVID-19.

Keywords: ACE2; BET inhibitors; SARS-CoV-2; TMPRSS2; androgen receptor.

Abstract

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