| Literature DB >> 33997789 |
April C Watt1,2, Paloma Cejas3,4,5, Molly J DeCristo6, Otto Metzger-Filho7, Enid Y N Lam1,2, Xintao Qiu3, Haley BrinJones6, Nikolas Kesten3, Rhiannon Coulson1,2, Alba Font-Tello3, Klothilda Lim3, Raga Vadhi3, Veerle W Daniels7, Joan Montero7,8, Len Taing3, Clifford A Meyer3, Omer Gilan1,2, Charles C Bell1,2, Keegan D Korthauer9,10, Claudia Giambartolomei11,12, Bogdan Pasaniuc11, Ji-Heui Seo3,7, Matthew L Freedman3,7, Cynthia Ma13, Matthew J Ellis14, Ian Krop7, Eric Winer7, Anthony Letai7, Myles Brown3,7, Mark A Dawson1,2,15, Henry W Long3,7, Jean J Zhao6,16,17, Shom Goel1,2,7.
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.Entities:
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Year: 2020 PMID： 33997789 PMCID： PMC8115221 DOI： 10.1038/s43018-020-00135-y
Source DB: PubMed Journal: Nat Cancer ISSN： 2662-1347