Discovery and Basic Research
Keith Robertson, PhD
Professor, Molecular Pharmacology and Experimental Therapeutics
Mayo Clinic, Minnesota
Tamer Fandy, PhD, BCGP, FCP
Professor & Chair, Department of Pharmaceutical & Adminstrative Sciences
University of Charleston
Charleston, West Virginia
Epigenetic modifications of DNA, RNA, and histone proteins are key mediators of organismal development and cellular differentiation. Most epigenetic marks are coordinated by a three-component system comprised of writer, reader, and eraser proteins that collectively regulate the dynamic and reversible cell-type specific deposition of marks, and mediate their effects on genome structure and transcriptional regulation. Deregulation and/or mutation of epigenetic writers, readers, and erasers leads to a disrupted epigenome that contributes directly to a wide array of human diseases, including cancer initiation and progression. The reversible nature of epigenetic changes, in contrast to genetic changes, creates novel avenues for therapy through development of inhibitors that target the epigenetic machinery. Similarly, the cell-type specific nature of epigenetic marks creates distinct advantages for biomarker and liquid biopsy development. These concepts will be reviewed. We use renal cell cancer as a paradigm for understanding how epigenetic regulator mutations drive cancer initiation and progression, and how these mutations can be targeted to advance individualized therapy directed against epigenetic regulator mutant cancers. Clear cell renal cell carcinoma (ccRCC) accounts for ~75% of kidney cancers and is the 8th leading cause of cancer death in the United States. After completion of The Cancer Genome Atlas (TCGA) Project, clinically actionable mutations were identified in virtually every solid tumor. One major exception, however, is RCC, where the current standard of care, checkpoint inhibitor and anti-VEGF therapy, does not take into account that ~50% of RCCs have mutations in chromatin modifiers, highlighting the need to identify how epigenome regulator mutations can be therapeutically targeted. Aside from the near ubiquitous loss of VHL, the mutational landscape of ccRCC is dominated by loss-of-function mutations in epigenetic regulators, including SETD2, BAP1, and PBRM1. SETD2, the sole factor responsible for trimethylating the histone H3 lysine 36 position, is linked to poor outcome and the promotion of metastasis. SETD2 and its mark H3K36me3 regulate a diverse array of biological processes ranging from transcriptional regulation, mRNA splicing, nucleosome positioning, and DNA repair, yet exactly how this regulator and its mark drive cancer phenotypes, particularly in ccRCC, remains unknown. Using a combination of engineered cell line models, biochemical methods, and primary patient tumors, coupled with transcriptome/epigenome analysis and interaction studies, we describe novel ways that SETD2 loss-of-function contributes to cancer initiation and progression. We also probe the interplay among multiple regulators of methylation at the H3K36 position to define novel pharmacologic paradigms that may lead to individualized therapies that target SETD2 mutant tumors.