PROJECT SUMMARY: CANCER EPIGENETICS RESEARCH PROGRAM The Sylvester Comprehensive Cancer Center (Sylvester) Cancer Epigenetics (CE) Research Program is composed of 26 members from nine departments and co-led by Ramin Shiekhattar, PhD, and David Lombard, MD, PhD, who bring complementary expertise and knowledge to the program. CE aims to pinpoint epigenetic factors and mechanisms that contribute to cancer risk, initiation, progression, and treatment resistance. It endeavors to develop innovative approaches to epigenetics research to mitigate the impact of cancer in Sylvester’s catchment area (CA), a highly diverse four-county area known as South Florida (SoFL). The CE program’s three specific aims are to 1) elucidate the oncogenic molecular mechanisms associated with epigenetic regulators that are mutated or dysregulated in cancer; 2) define the enhancer and transcriptional reprogramming imposed by aberrant signal transduction and altered metabolism in cancer; and 3) identify and validate epigenetic mechanisms and targets as the basis for biomarker development and therapeutic intervention. CE members receive $4.6M in annual direct peer-reviewed funding, with $1.6M from the NCI and $1.5M in 11 multi-principal investigator (MPI) grants. During the current reporting period (6/1/2018-5/31/2023), CE members published 252 cancer-related papers; 20% represent intra-programmatic, 32% represent inter- programmatic, and 82% reflect multi-institutional collaborations. Forty-four percent of CE’s publications are in top-tier journals with an impact factor greater than ten. CE works collaboratively with Tumor Biology to understand the interplay between oncogenic signaling and epigenetic dysregulation in cancer, with Cancer Control to understand how environmental and socio-economic disparities impact the epigenome and influence cancer initiation and progression, and with Translational and Clinical Oncology to translate findings made by CE researchers into clinical trials. These efforts are supported by NCI and NIH R01 grants, Department of Defense awards, and a newly awarded Leukemia and Lymphoma Society Specialized Center of Research program project grant. CE’s research efforts leverage Sylvester’s Shared Resources (SRs), particularly the Onco-Genomics, Flow Cytometry, Cancer Modeling, Biospecimen, and Biostatistics and Bioinformatics SRs. Major CE discoveries during the reporting period include the 1) paradigm-shifting demonstration that the Polycomb Repressive Complex 1 promotes estrogen receptor-dependent oncogenic gene expression in breast cancer; 2) elucidation of epigenetic mechanisms underlying the changes in enhancer function in hematopoietic stem cells in the aging process, relevant to Sylvester’s aging and cancer cross-cutting theme and its large and diverse elderly population in its CA; and 3) demonstration that targeting LSD1 can potentiate the clinical activity of differentiation therapy in patients with myelodysplastic syndrome or acute myeloid leuk...