Journal article
CDK4/6 inhibition reprograms the breast cancer enhancer landscape by stimulating AP-1 transcriptional activity
AC Watt, P Cejas, MJ DeCristo, O Metzger-Filho, EYN Lam, X Qiu, H BrinJones, N Kesten, R Coulson, A Font-Tello, K Lim, R Vadhi, VW Daniels, J Montero, L Taing, CA Meyer, O Gilan, CC Bell, KD Korthauer, C Giambartolomei Show all
Nature Cancer | NATURE PORTFOLIO | Published : 2021
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 endogenou..
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Awarded by National Cancer Institute
Funding Acknowledgements
This work is supported by the National Health and Medical Research Council of Australia (Investigator Grant GNT1177357 to S.G.); Susan G. Komen for the Cure (to I.K. and M.B. and CCR18547966 to S.G.); the Breast Cancer Alliance (Young Investigator Grant to S.G.); the Royal Australasian College of Physicians (Research Establishment Fellowship to S.G.); Eli Lilly and Co (to S.G.); the NIH/NCI (P50 CA168504 to S.G., I.K., E.W. and J.J.Z.; R35 CA210057 to J.J.Z.; P50 CA165962-06A1 to J.J.Z.; P01CA080111 to M.B.; R01CA193910 to M.L.F.; R02HG005220 to K.D.K. (PI Rafael A. Irizarry), R01GM083084 to K.D.K. (PI Rafael A. Irizarry), U41HG004059 to K.D.K. (PI Martin T. Morgan)); the US Department of Defense CDMRP (W81XWH-18-1-0491 to J.J.Z.); the Breast Cancer Research Foundation (BCRF-18-179 to J.J.Z. and O.M.-F.), the Ministry of Economy and Competitiveness (Instituto de Salud Carlos III) PI18-01604 to P.C.; the Chan Zuckerberg Initiative (DAF grant 2018-183142 to K.D.K. (PI Rafael A. Irizarry)); Stand Up To Cancer (SU2C) and The V Foundation (TVF) SU2C-TVF Convergence Scholar Awards (D2015-037 to J.M.); Ramon y Cajal Programme, Ministerio de Economia y Competitividad (RYC-2015-18357 to J.M.); Terri Brodeur Breast Cancer Foundation (to V.W.D.); and the European Union's Horizon 2020 Research and Innovation Programme (Marie Skodowska-Curie grant agreement no. 754490 to C.G. and the MINDED project).