The Role of REV-ERB Receptors in Cancer Pathogenesis

Abstract

REV-ERB receptors are members of the nuclear receptor superfamily of proteins, which act as both intracellular receptors and transcription factors, therefore modulating the expression of target genes. REV-ERBs act as transcription repressors because of their unique structure. Their predominant role involves the control of peripheral circadian rhythmicity by participating in a transcription–translation feedback loop with other major clock genes. Regarding their role in cancer pathogenesis, recent studies in various cancerous tissues have revealed that their expression was downregulated in the majority of the cases. Dysregulation of their expression was also implicated in cancer-associated cachexia. The pharmacological restoration of their effects is feasible with synthetic agonists, which have been explored in preclinical studies but with scarce data. There is a need for further investigation, primarily with mechanistic studies, on the effect of the REV-ERB-induced circadian rhythm deregulation in carcinogenesis and cancer-related systemic effects, such as cachexia, in order to address the potential of relevant therapeutic implications.

Identification of a Dual Autophagy and REV-ERB Inhibitor with in Vivo Anticancer Efficacy

“…The crude was purified by flash column chromatography (SiO 2 ), eluting with CH 2 Cl 2 /MeOH from 100 to 96:4 to afford 18 as yellow oil (0.049 g, 11% over 4 steps). UPLC/MS (method B): (19). Compound 19 was prepared according to the general procedure N using aldehyde 40l (0.032 g, 0.13 mmol), amine 30e (0.023 g, 0.13 mmol), and NaBH(OAc) 3 (0.054 g, 0.26 mmol) in anhydrous CH 2 Cl 2 (1.30 mL).…”

“…An additional strategy to overcome the limitations deriving from the need of high doses of CQ and HCQ for inhibiting tumor growth is represented by a multitarget approach targeting both autophagy and pathways associated with autophagy-dependent cancer cell death. We previously reported that REV-ERB, a nuclear receptor regulating circadian rhythm and metabolism, − plays a role in sustaining cancer cell survival when the autophagy flux is compromised . Indeed, pharmacological inhibition of REV-ERB significantly enhanced the cytotoxic activity of CQ against breast cancer cells, and cells from different cancer types knocked-down for REV-ERB were more sensitive to CQ-induced cell death. , In addition, the knockdown of the essential autophagy gene ATG5 in breast cancer cells enhanced the toxicity of the REV-ERB antagonist, SR8278 (Figure ), further indicating that REV-ERB inhibition induces cell death when autophagy is inhibited …”

Investigating REV-ERBβ Binding Pocket Dynamics with Implications for Rational Design of Small Molecule Modulators

“…Efforts have been made to experimentally discover small molecules modulating the REV-ERB activity 8 . The small molecules discovered have been pharmacologically used to regulate the REV-ERB activity in several disease models such as Alzheimer’s, Duchenne Muscular Dystrophy (DMD), type-2 diabetes mellitus (T2DM), obesity, HIV replication cycle, non-alcoholic fatty liver disease (NAFLD), and cancer 9–17 . While most studies have reported the role of small molecules on α isoform, only a few studies have looked at the β isoform 8, 18, 19 .…”