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

April C. Watt, Paloma Cejas, Molly J. DeCristo, Otto Metzger-Filho, Enid Y.N. Lam, Xintao Qiu, Haley BrinJones, Nikolas Kesten, Rhiannon Coulson, Alba Font-Tello, Klothilda Lim, Raga Vadhi, Veerle W. Daniels, Joan Montero, Len Taing, Clifford A. Meyer, Omer Gilan, Charles C. Bell, Keegan D. Korthauer, Claudia GiambartolomeiBogdan Pasaniuc, Ji Heui Seo, Matthew L. Freedman, Cynthia Ma, Matthew J. Ellis, Ian Krop, Eric Winer, Anthony Letai, Myles Brown, Mark A. Dawson, Henry W. Long, Jean J. Zhao, Shom Goel

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

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 are enriched for proximity to interferon-driven genes. Mechanistically, CDK4/6 inhibition increases the level of several activator protein-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.

Original languageEnglish
Pages (from-to)34-48
Number of pages15
JournalNature Cancer
Volume2
Issue number1
DOIs
StatePublished - Jan 2021

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