Watt, April CCejas, PalomaDeCristo, MollyMetzger, OttoLam, EnidQiu, XintaoBrinJones, HaleyKesten, NikolasCoulson, RhiannonAlba, Font-TelloLim, KlothildaVadhi, RagaDaniels, Veerle WMontero, JoanTaing, LenMeyer, CliffordGilan, OmerBell, Charles CKorthauer, KeeganGiambartolomei, ClaudiaPasaniuc, BogdanSeo, Ji-HeuiFreedman, Matthew LMa, CynthiaEllis, Matthew JKrop, IanWiner, EricLetai, AnthonyBrown, MylesDawson, Mark ALong, Henry WZhao, JeanGoel, Shom2023-08-292020-11-09Watt, April C, Paloma Cejas, Molly DeCristo, Otto Metzger, Enid Lam, Xintao Qiu, Haley BrinJones et al. "CDK4/6 inhibition reprograms the breast cancer enhancer landscape by stimulating AP-1 transcriptional activity." Nat Cancer 2, no. 1 (2020): 34-48. DOI: 10.1038/s43018-020-00135-y2662-1347https://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37376920Cyclin-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.en-USCancer ResearchOncologyJournal Article2023-08-2910.1038/s43018-020-00135-y