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Watt, April C., Cejas, Paloma, DeCristo, Molly J., Metzger-Filho, Otto, Lam, Enid Y. N., 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, (2021). CDK4/6 inhibition reprograms the breast cancer enhancer landscape by stimulating AP-1 transcriptional activity Nature Cancer 2, 34-48

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.

Keywords: Breast cancer, Cancer, Cancer therapy, Epigenetics

Vodovotz, Y., Barnard, N., Hu, F. B., Jakicic, J., Lianov, L., Loveland, D., Buysse, D., Szigethy, E., Finkel, T., Sowa, G., Verschure, P., Williams, K., Sanchez, E., Dysinger, W., Maizes, V., Junker, C., Phillips, E., Katz, D., Drant, S., Jackson, R. J., Trasande, L., Woolf, S., Salive, M., South-Paul, J., States, S. L., Roth, L., Fraser, G., Stout, R., Parkinson, M. D., (2020). Prioritized research for the prevention, treatment, and reversal of chronic disease: recommendations from the lifestyle medicine research summit Frontiers in Medicine 7, 585744

Declining life expectancy and increasing all-cause mortality in the United States have been associated with unhealthy behaviors, socioecological factors, and preventable disease. A growing body of basic science, clinical research, and population health evidence points to the benefits of healthy behaviors, environments and policies to maintain health and prevent, treat, and reverse the root causes of common chronic diseases. Similarly, innovations in research methodologies, standards of evidence, emergence of unique study cohorts, and breakthroughs in data analytics and modeling create new possibilities for producing biomedical knowledge and clinical translation. To understand these advances and inform future directions research, The Lifestyle Medicine Research Summit was convened at the University of Pittsburgh on December 4–5, 2019. The Summit's goal was to review current status and define research priorities in the six core areas of lifestyle medicine: plant-predominant nutrition, physical activity, sleep, stress, addictive behaviors, and positive psychology/social connection. Forty invited subject matter experts (1) reviewed existing knowledge and gaps relating lifestyle behaviors to common chronic diseases, such as cardiovascular disease, diabetes, many cancers, inflammatory- and immune-related disorders and other conditions; and (2) discussed the potential for applying cutting-edge molecular, cellular, epigenetic and emerging science knowledge and computational methodologies, research designs, and study cohorts to accelerate clinical applications across all six domains of lifestyle medicine. Notably, federal health agencies, such as the Department of Defense and Veterans Administration have begun to adopt “whole-person health and performance” models that address these lifestyle and environmental root causes of chronic disease and associated morbidity, mortality, and cost. Recommendations strongly support leveraging emerging research methodologies, systems biology, and computational modeling in order to accelerate effective clinical and population solutions to improve health and reduce societal costs. New and alternative hierarchies of evidence are also be needed in order to assess the quality of evidence and develop evidence-based guidelines on lifestyle medicine. Children and underserved populations were identified as prioritized groups to study. The COVID-19 pandemic, which disproportionately impacts people with chronic diseases that are amenable to effective lifestyle medicine interventions, makes the Summit's findings and recommendations for future research particularly timely and relevant.

Keywords: Chronic disease, Epigenetics, In silico modeling, Inflammation, Lifestyle medicine, Nutrition, Physical activity, Research methodologies