Abstract
Transcriptional dysregulation is a hallmark of cancer and can be an essential driver of cancer initiation and progression. Loss of transcriptional control can cause cancer cells to become dependent on certain regulators of gene expression. Bromodomain and extraterminal domain (BET) proteins are epigenetic readers that regulate the expression of multiple genes involved in carcinogenesis. BET inhibitors (BETis) disrupt BET protein binding to acetylated lysine residues of chromatin and suppress the transcription of various genes, including oncogenic transcription factors. Phase I and II clinical trials demonstrated BETis’ potential as anticancer drugs against solid tumours and haematological malignancies; however, their clinical success was limited as monotherapies. Emerging treatment-associated toxicities, drug resistance and a lack of predictive biomarkers limited BETis’ clinical progress. The preclinical evaluation demonstrated that BETis synergised with different classes of compounds, including DNA repair inhibitors, thus supporting further clinical development of BETis. The combination of BET and PARP inhibitors triggered synthetic lethality in cells with proficient homologous recombination. Mechanistic studies revealed that BETis targeted multiple essential homologous recombination pathway proteins, including RAD51, BRCA1 and CtIP. The exact mechanism of BETis’ anticancer action remains poorly understood; nevertheless, these agents provide a novel approach to epigenome and transcriptome anticancer therapy.
Highlights
Zdzislawa RobaszkiewiczCell identity and its proper functioning are determined by the transcriptome
BRD4 and BRDT contain a C-terminal motif (CTM) that the presence of two N-terminal bromodomains, BD1 and BD2, and an extraterminal domain facilitates the recruitment of transcriptional regulators, including the positive transcrip(ET) (Figure 1) [4,5,6]
Possible mechanisms of resistance to BET inhibitors (BETis) encompass AMPK-ULK1mediated autophagy in acute myeloid leukaemia (AML) [76,77], nuclear factor κB (NF-κB) in colorectal cancer [78], PP2A phosphatase and BCL2L1/BCL-X in breast cancer [79], the GLI2-dependent Hedgehog pathway in pancreatic cancer [80] and kinome reprogramming in ovarian cancer [81], among others
Summary
Cell identity and its proper functioning are determined by the transcriptome. The single-cell transcriptome is regulated by tens of thousands of promoter and enhancer regions and a few hundred super-enhancer—clusters of enhancers binding master transcription factors and mediators [1,2,3]. The control of the transcriptome is even more complex given epigenetic changes, including noncoding RNA synthesis, DNA methylation and histone modification. Histone acetylation at lysine residues is a reversible and highly dynamic modification frequently disturbed in cancer cells, making it an attractive anticancer therapy target. Loss of transcriptional control leads to changes in gene expression, which could be a driving force behind carcinogenesis. Defective DNA damage response (DDR) and repair pathways are cancer cells’ common features that trigger disease initiation and progression. The efficacy of DNA damage repair is provided by the proper structure of repair proteins and a sufficient amount of DDR and repair pathway members. We discuss the role of epigenetic readers in the transcriptional control of DNA repair genes and the implications for carcinogenesis and anticancer therapy.
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