Keck School of Medicine Events
Keck School of Medicine of USC Research Seminar Series
Reversing the Oncogenic Roles of Misdirected Chromatin Remodeling
Monday, September 23, 2013
11:30 AM - 1:00 PM
Aresty Auditorium, Norris Research Tower.
Cigall Kadoch, PhD, Howard Hughes Medical Institute Postdoctoral Fellow, Departments of Pathology and Developmental Biology Stanford University School of Medicine, will be presenting. Dr. Peter Jones will be hosting this event and introducing the speaker.
Recent exon- and genome-wide sequencing studies of human cancers have revealed frequent mutations in genes encoding subunits of mSWI/SNF or BAF complexes and implicated them as tumor suppressors. Indeed, we estimate that they are mutated in >20% of human cancers (Kadoch et al, Nature Genetics 2013). Interestingly, the subunits most commonly mutated are not required for chromatin remodeling in vitro and thus may contribute to chromatin regulation in a novel way. One difficultly in understanding the oncogenic role(s) of these complexes is distinguishing primary driving mutations from passenger mutations. To investigate the mechanism underlying oncogenesis, we studied human synovial sarcoma (SS), in which transformation results from a remarkably precise and uniform translocation of exactly 78 amino acids of SSX (SSX1, 2 or 4) to the SS18 protein. In a proteomic study we discovered that SS18 is a dedicated, non-exchangeable subunit of BAF complexes. We demonstrate that the hallmark SS18-SSX fusion incorporates into BAF complexes, evicting both the wild-type SS18 protein and the tumor suppressor, hSNF5 (BAF47), which is known to be biallelically inactivated in malignant rhabdoid tumors. The altered complex binds the Sox2 locus, reversing polycomb-mediated H3K27me3 repression and activating Sox2. Sox2 is uniformly expressed in SS tumors and is essential for proliferation. Remarkably, increasing the concentration of wild-type SS18 leads to reassembly of wild-type complexes, retargeting of BAF complexes, returned polycomb-mediated repression at the Sox2 locus and cessation of SS cell proliferation. This mechanism of transformation depends on a two amino acid hydrophilic region of SSX and hence provides a potential foundation for therapeutic intervention. Cigall Kadoch, Ph.D. completed her graduate studies at the Stanford University School of Medicine and Howard Hughes Medical Institute in the Laboratory of Dr. Gerald Crabtree. Here, Dr. Kadoch worked to identify and characterize novel components of a chromatin remodeling complex, among them, SS18, which is translocated in synovial sarcoma (t(X;18)), resulting in the hallmark SS18-SSX oncogenic fusion protein. Through a series of biochemical and mechanistic investigations, Kadoch uncovered a mechanism of oncogenesis driven by SS18-SSX mediated perturbation to mSWI/SNF (BAF) chromatin remodeling complexes. Her current efforts at the Broad Institute of Harvard and MIT, involve small molecule therapeutic discovery studies in synovial sarcoma as well as further mechanistic investigations of misdirected chromatin remodeling in human cancers.
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