1. CDK4/6 inhibition reprograms the breast cancer enhancer landscape by stimulating AP-1 transcriptional activity
- Author
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Watt, April C, Cejas, Paloma, DeCristo, Molly J, Metzger-Filho, Otto, Lam, Enid YN, Qiu, Xintao, BrinJones, Haley, Kesten, Nikolas, Coulson, Rhiannon, Font-Tello, Alba, Lim, Klothilda, Vadhi, Raga, Daniels, Veerle W, Montero, Joan, Taing, Len, Meyer, Clifford A, Gilan, Omer, Bell, Charles C, Korthauer, Keegan D, Giambartolomei, Claudia, Pasaniuc, Bogdan, Seo, Ji-Heui, Freedman, Matthew L, Ma, Cynthia, Ellis, Matthew J, Krop, Ian, Winer, Eric, Letai, Anthony, Brown, Myles, Dawson, Mark A, Long, Henry W, Zhao, Jean J, and Goel, Shom
- Subjects
Genetics ,Breast Cancer ,Cancer ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Animals ,Breast Neoplasms ,Cell Cycle Checkpoints ,Cyclin-Dependent Kinase 4 ,Female ,Genes ,cdc ,Humans ,Mice ,Transcription Factor AP-1 - Abstract
Pharmacologic inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) were designed to induce cancer cell cycle arrest. Recent studies have suggested that these agents also exert other effects, influencing cancer cell immunogenicity, apoptotic responses, and differentiation. Using cell-based and mouse models of breast cancer together with clinical specimens, we show that CDK4/6 inhibitors induce remodeling of cancer cell chromatin characterized by widespread enhancer activation, and that this explains many of these effects. The newly activated enhancers include classical super-enhancers that drive luminal differentiation and apoptotic evasion, as well as a set of enhancers overlying endogenous retroviral elements that is enriched for proximity to interferon-driven genes. Mechanistically, CDK4/6 inhibition increases the level of several Activator Protein-1 (AP-1) transcription factor proteins, which are in turn implicated in the activity of many of the new enhancers. Our findings offer insights into CDK4/6 pathway biology and should inform the future development of CDK4/6 inhibitors.
- Published
- 2021