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

  • Nat Cancer. 2021 Jan;2(1):34-48. doi: 10.1038/s43018-020-00135-y.
April C Watt  1  2 ,  Paloma Cejas  3  4  5 ,  Molly J DeCristo  6 ,  Otto Metzger-Filho  7 ,  Enid Y N Lam  1  2 ,  Xintao Qiu  3 ,  Haley BrinJones  6 ,  Nikolas Kesten  3 ,  Rhiannon Coulson  1  2 ,  Alba Font-Tello  3 ,  Klothilda Lim  3 ,  Raga Vadhi  3 ,  Veerle W Daniels  7 ,  Joan Montero  7  8 ,  Len Taing  3 ,  Clifford A Meyer  3 ,  Omer Gilan  1  2 ,  Charles C Bell  1  2 ,  Keegan D Korthauer  9  10 ,  Claudia Giambartolomei  11  12 ,  Bogdan Pasaniuc  11 ,  Ji-Heui Seo  3  7 ,  Matthew L Freedman  3  7 ,  Cynthia Ma  13 ,  Matthew J Ellis  14 ,  Ian Krop  7 ,  Eric Winer  7 ,  Anthony Letai  7 ,  Myles Brown  3  7 ,  Mark A Dawson  1  2  15 ,  Henry W Long  3  7 ,  Jean J Zhao  6  16  17 ,  Shom Goel  1  2  7
Affiliations
  • 1. Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
  • 2. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
  • 3. Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
  • 4. Translational Oncology Laboratory, Hospital La Paz Institute for Health Research (IdiPAZ), Madrid, Spain.
  • 5. CIBERONC CB16/12/00398, La Paz University Hospital, Madrid, Spain.
  • 6. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
  • 7. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
  • 8. Institute for Bioengineering of Catalonia, Spain.
  • 9. Department of Data Sciences, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
  • 10. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America.
  • 11. Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
  • 12. Istituto Italiano di Tecnologia (IIT), Genoa, Italy.
  • 13. Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.
  • 14. Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas, USA.
  • 15. Centre for Cancer Research, University of Melbourne, Parkville, Victoria, Australia.
  • 16. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, United States of America.
  • 17. The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
PMID: 33997789 DOI: 10.1038/s43018-020-00135-y
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.

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