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 are a class of small molecule compounds that target proteins with key roles in gene regulation, as ‘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 targets (10-12). However, recent reports have 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 simultaneously 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.
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- 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.
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- 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
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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.
Current contact information:
Dr. Chakrapani Tripathi, Senior Scientist
455 Mission Bay Boulevard South,
San Francisco, CA 94158.
Current contact information:
Dr. Shilan Zhang,
Department of Cardiovascular Medicine,
Shanghai Tenth People's Hospital,
Tongji University School of Medicine.
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.