SR8278 inhibits cell proliferation independent of REV-ERB

Background The small molecule SR8278 was initially identified as an antagonist of the REV-ERB (reverse c-ERBAa) nuclear receptor proteins, which play an important role in metabolism and circadian rhythms. Though SR8278 has been shown to have beneficial physiological effects in a variety of preclinical disease contexts, its impact on gene expression and cell proliferation in keratinocytes has not previously been examined. Methods An RNA-seq analysis was used to identify genes differentially impacted by SR8278 treatment in human HaCaT keratinocytes, which was confirmed by RT-qPCR and western blotting. Cell growth and viability assays were further used to examine cell proliferation in HaCaT and other cell lines. CRISPR/Cas9 genome editing was used to generate cells lacking REV-ERBα and β. Results RNA-seq analysis indicated genes involved in the G1/S transition of the cell cycle were significantly impacted by SR8278 treatment, which was confirmed via RT-qPCR and western blotting. Cell proliferation assays showed that SR8278 slowed cell growth but did not induce apoptosis. Finally, the knockout of the REV-ERBs did not impact the effect of SR8278 on gene expression and cell proliferation. Conclusions We conclude that the anti-proliferative effects of SR8278 are not mediated by the REV-ERB proteins, and thus care should be taken when interpreting studies involving this compound unless complementary genetic approaches are also shown.