Targeting ACE2-BRD4 in Cancer and COVID-19

S Zhang, S Kapoor, C Tripathi, J Tovar Perez, N Mohan, WM Dashwood, K Zhang, P Rajendran & R Dashwood
Targeting ACE2-BRD4 in Cancer and COVID-19
Like

Cancer patients are at an increased risk of COVID-19 due to their immunocompromised conditions (1), including subjects with gastrointestinal (GI) pathologies (2). Patients with COVID-19 exhibit GI symptoms such as nausea, vomiting and diarrhea (3), and SARS-CoV-2 RNA can persist in fecal samples from affected individuals (4). The ACE2 protein is present on the surface of many cells in the human body, including in the GI and respiratory tracts (5,6), and is a key entry receptor for SARS-CoV-2 virus into colonocytes and nasal epithelial cells via the Spike glycoprotein (7). Interestingly, ACE2 is expressed at high levels in various malignancies, including colorectal cancer (8). This raises a concern that patients with colorectal cancer might be at increased risk of contracting COVID-19 due to their high levels of ACE2 expression.

Bromodomain and extraterminal domain (BET) inhibitors target the ‘readers’ of acetylated lysine residues on histone and non-histone proteins (9). In the context of cancer therapy, BET inhibitors downregulate MYC and other oncogenic factors (10-12). However, recent reports provided conflicting viewpoints regarding the use of pan-BET inhibitors in targeting ACE2 overexpression. In lung cancer cells, the BET protein BRD2 was identified as 'proviral' and positively regulated expression of the ACE2 receptor, whereas BRD4 was ‘antiviral’ through changes in gene expression profiles, including interferon signaling (13). Thus, anticancer agents targeting both BRD2 and BRD4 might be disadvantageous in the setting of COVID-19 infection.

Colorectal cancer datasets predicted that high expression of both ACE2 and BRD4 mRNAs was associated with significantly reduced patient survival compared with low ACE2 plus low BRD4 levels (14,15). No such relationships were observed for ACE2 and BRD2. In a panel of human colon cancer cells, there was moderate to high constitutive expression of ACE2, BRD2 and BRD4 proteins compared with normal colonic epithelial cells. RNAi-mediated knockdown of ACE2 or loss of ACE2 upon pharmacologic BET inhibition with JQ1, MZ1 or dBET6 (12,16,17) increased DNA damage/repair markers, reduced cell viability/colony formation, and enhanced apoptosis. Morphological and mechanistic readouts were reversed following transient transfection of an ACE2 expression construct, which dose-dependently circumvented the apoptosis induction associated with decreased BRD4 levels upon dBET6 treatment. Antitumor activity of dBET6 in vivo coincided with a near-complete loss of tumor-associated BRD4 and ACE2 protein expression (12,15).  

Our findings and prior reports highlight the yin-yang nature of targeting ACE2 and BET proteins in cancer etiology. In human colon cancer cells, an apparent oncogenic role was implicated for ACE2 via crosstalk with BRD4 and c-Myc (15). In human lung epithelial cells, BET antagonists inhibited SARS-CoV-2 infection (18), whereas in lung cancer cells proviral versus antiviral roles were identified for BRD2 and BRD4, respectively (13). Next-generation therapeutics that selectively target BRD2 or BRD4 will help to clarify risk-benefit in the context of prior versus concurrent BET inhibitor treatment in colorectal cancer patients with SARS-CoV-2 infection.     

References

  1. A. Fendler et al. COVID-19 vaccines in patients with cancer: immunogenicity, efficacy and safety. Nat Rev Clin Oncol 2022;19(6):385-401.
  2. H. Zhang et al. Outcomes of novel coronavirus disease 2019 (COVID-19) infection in 107 patients with cancer from Wuhan, China. Cancer 2020;126(17):4023-4031.
  3. W. Redd et al. Prevalence and characteristics of gastrointestinal symptoms in patients with severe acute respiratory syndrome coronavirus 2 infection in the United States: a multicenter cohort study. Gastroenterology 2020;159(2):765-767.
  4. Y. Wu et al. Prolonged presence of SARS-CoV-2 viral RNA in faecal samples. Lancet Gastroenterol Hepatol 2020;5(5):434-435.
  5. F. Xiao et al. Evidence for gastrointestinal infection of SARS-CoV-2. Gastroenterology 2020;158(6):1831-1833.e3.
  6. N. Zamorano Cuervo & N. Grandvaux (2020) ACE2: evidence of role as entry receptor for SARS-CoV-2 and implications in comorbidities. eLife 2020;9:e61390.
  7. W. Li et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 2003;426(6965):450-454.
  8. C. Liu et al. High expression of ACE2 and TMPRSS2 and clinical characteristics of COVID-19 in colorectal cancer patients. npj Precision Oncol 2021;5(1):1.
  9. T. Fujisawa & P. Filippakopoulos. Functions of bromodomain-containing proteins and their roles in homoeostasis and cancer. Nat Rev Mol Cell Biol 2017;18(4):246-262.
  10. P. Mazur et al. Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma. Nat Med 2015;21(10):1163-1171.
  11. P. Rajendran et al. Acetylation of CCAR2 establishes a BET/BRD9 acetyl switch in response to combined deacetylase and bromodomain inhibition. Cancer Res 2019;79(5):918-927.
  12. S. Kapoor et al. Deacetylase plus bromodomain inhibition downregulates ERCC2 and suppresses the growth of metastatic colon cancer cells. Cancers (Basel) 2021;13(6):1438.
  13. I. Chen et al. Viral E protein neutralizes BET protein-mediated post-entry antagonism of SARS-CoV-2. Cell Rep 2022;40(3):111088.
  14. S. Li et al. The impact of ACE2 and co-factors on SARS-CoV-2 infection in colorectal cancer. Clin Transl Med 2022;12(7):e967.
  15. S. Zhang et al. Targeting ACE2-BRD4 crosstalk in colorectal cancer and the deregulation of DNA repair and apoptosis. npj Prec Oncol 2023;7(1):20. https://doi.org/10.1038/s41698-023-00361-4
  16. P. Filippakopoulos et al. Selective inhibition of BET bromodomains. Nature 2010;468(7327):1067-73.
  17. G. Winter et al. BET bromodomain proteins function as master transcriptional elongation factors independent of CDK9 recruitment. Mol Cell 2017;67(1):5-18.e19.
  18. Y. Qiao et al. Targeting transcriptional regulation of SARS-CoC-2 entry factors ACE2 and TMPRSS2. Proc Natl Acad Sci USA 2021;118(1):e2021450118.

Please sign in or register for FREE

If you are a registered user on Research Communities by Springer Nature, please sign in

Go to the profile of Rod Dashwood
12 months ago

Acknowledgements | Nivedhitha Mohan provided initial drafts of the text and associated artwork, and was a major contributor to the blog, along with further edits by other coauthors, in particular, Dr. Praveen Rajendran.

Go to the profile of Rod Dashwood
12 months ago

Current contact information:

Dr. Chakrapani Tripathi, Senior Scientist 

Nektar Therapeutic,

455 Mission Bay Boulevard South,

San Francisco, CA 94158.

Email: chakrapani010@gmail.com

          ctripathi@nektar.com

Phone: 3179353701

Go to the profile of Rod Dashwood
12 months ago

Current contact information:

Dr. Shilan Zhang,

Department of Cardiovascular Medicine,

Shanghai Tenth People's Hospital,

Tongji University School of Medicine.

Email: slzhang7@sina.com

Go to the profile of Rod Dashwood
11 months ago

Supplementary figures | Constitutive expression of ACE2 in human colon cancer cells; ACE2 regulates DNA repair, cell viability and apoptosis in SW480 and SW620 human colon cancer cells; forced expression of ACE2 increases endogenous BRD4 and c-Myc in SW480 cells; BET inhibitors and degraders lower endogenous ACE2 and c-Myc expression in human colon cancer cells; ACE2 overexpression in rat colon adenomas; gating strategies for cell sorting via FACS.

Subscribe to the Topic

Cancer Biology
Life Sciences > Biological Sciences > Cancer Biology

Related Collections

With collections, you can get published faster and increase your visibility.

Innovations in cancers of the central nervous system

This Collection invites research on tumors involving the central nervous system, including primary glial tumors, meningiomas and metastatic tumors in adults.

Publishing Model: Open Access

Deadline: Mar 01, 2024

AI in precision oncology

This Collection is a partnership between npj Precision Oncology and npj Breast Cancer. It will bring together articles on all facets of AI in cancer research.

Publishing Model: Open Access

Deadline: Apr 19, 2024