A-Z of Epigenetic Readers: Targeting Alternative Splicing and Histone Modification Variants in Cancer.

Epigenetic 'reader' proteins, which have evolved to interact with specific chromatin modifications, play pivotal roles in gene regulation. There is growing interest in the alternative splicing mechanisms that affect the functionality of such epigenetic readers in cancer etiology. The current review considers how deregulation of epigenetic processes and alternative splicing events contribute to pathophysiology. An A-Z guide of epigenetic readers is provided, delineating the antagonistic 'yin-yang' roles of full-length versus spliced isoforms, where this is known from the literature. The examples discussed underscore the key contributions of epigenetic readers in transcriptional regulation, early development, and cancer. Clinical implications are considered, offering insights into precision oncology and targeted therapies focused on epigenetic readers that have undergone alternative splicing events during disease pathogenesis. This review underscores the fundamental importance of alternative splicing events in the context of epigenetic readers while emphasizing the critical need for improved understanding of functional diversity, regulatory mechanisms, and future therapeutic potential.

Targeting ACE2-BRD4 crosstalk in colorectal cancer and the deregulation of DNA repair and apoptosis.

ACE2 overexpression in colorectal cancer patients might increase susceptibility to SARS-CoV-2 infection. We report that knockdown, forced overexpression, and pharmacologic inhibition in human colon cancer cells targeted ACE2-BRD4 crosstalk to mediate marked changes in DNA damage/repair and apoptosis. In colorectal cancer patients for whom high ACE2 plus high BRD4 expression is predictive of poor survival, pan-BET inhibition would need to consider proviral/antiviral actions of different BET proteins during SARS-CoV-2 infection.

Targeting Epigenetic 'Readers' with Natural Compounds for Cancer Interception.

Natural compounds from diverse sources, including botanicals and commonly consumed foods and beverages, exert beneficial health effects via mechanisms that impact the epigenome and gene expression during disease pathogenesis. By targeting the so-called epigenetic 'readers', 'writers', and 'erasers', dietary phytochemicals can reverse abnormal epigenome signatures in cancer cells and preneoplastic stages. Thus, such agents provide avenues for cancer interception via prevention or treatment/therapeutic strategies. To date, much of the focus on dietary agents has been directed towards writers (e.g., histone acetyltransferases) and erasers (e.g., histone deacetylases), with less attention given to epigenetic readers (e.g., BRD proteins). The drug JQ1 was developed as a prototype epigenetic reader inhibitor, selectively targeting members of the bromodomain and extraterminal domain (BET) family, such as BRD4. Clinical trials with JQ1 as a single agent, or in combination with standard of care therapy, revealed antitumor efficacy but not without toxicity or resistance. In pursuit of second-generation epigenetic reader inhibitors, attention has shifted to natural sources, including dietary agents that might be repurposed as 'JQ1-like' bioactives. This review summarizes the current status of nascent research activity focused on natural compounds as inhibitors of BET and other epigenetic 'reader' proteins, with a perspective on future directions and opportunities.