학술논문
CDK4/6 inhibition reprograms the breast cancer enhancer landscape by stimulating AP-1 transcriptional activity
Document Type
article
Author
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; Goel, Shom
Source
Nature Cancer. 2(1)
Subject
Language
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.