CDK4/6 inhibition reprograms the breast cancer enhancer landscape by stimulating AP-1 transcriptional activity

Abstract

Cyclin-dependent kinases 4 and 6 (CDK4/6) mediate cancer cell proliferation, and CDK4/6 inhibitors effectively induce cancer cell cycle arrest. Recent reports have suggested that CDK4/6 inhibition might also exert other effects in cancer cells, impacting their immunogenicity, apoptotic responses, and differentiation. Using breast cancer cell lines, mouse models, and clinical specimens, we show that CDK4/6 inhibition induces dramatic remodelling of cancer cell chromatin, characterised by widespread enhancer activation, and that this explains many of these effects. The newly activated enhancers include classical super-enhancers that are associated with luminal differentiation and apoptotic evasion, as well as a smaller set of enhancers overlying endogenous retroviral elements that is predicted to enhance tumour cell immunogenicity. Importantly, CDK4/6 inhibition increases the level of several Activator Protein-1 (AP-1) transcription factor family members in breast cancer cells, and AP-1 factors are implicated in the activity of many of these new enhancers. Our findings offer new insights into CDK4/6 pathway biology and have implications for the future development of CDK4/6 inhibitors.