Epithelial ovarian cancer is the most frequent cause of gynecologic malignancy-related mortality in women in the United States; 22,240 new cases and 14,070 deaths are estimated to have occurred thus far in 2018. A growing emphasis in ovarian cancer drug discovery efforts has been on targeting epigenome. However, challenges in target identification and characterization have resulted in a narrow focus on the development of drugs for ovarian cancer therapy. Ovarian tumorigenesis is driven by the acquisition of somatic alterations in the genome including copy number alterations, single nucleotide substitutions, small insertions/deletions, and structural rearrangements. Recent genomic studies have shown that the genes involved in epigenetic regulation are altered in ovarian cancer at unexpectedly high frequencies, suggesting that certain genes encoding the epigenetic regulatory proteins may serve as driver genes during ovarian cancer development. SWItch/Sucrose Non-Fermentable (SWI/SNF), a multi-subunit nucleosome remodeling complex, possesses an ATPase activity and alters the position of nucleosomes along DNA. Constituting a large (∼2 MDa) protein complex, mammalian SWI/SNF (mSWI/SNF) is polymorphic assemblies of 12~15 subunits encoded by 29 genes. SWI/SNF regulates DNA accessibility by alteration of nucleosome positioning and occupancy in an ATP-dependent manner, therefore playing critical roles in maintaining chromatin architecture and appropriate gene expression during development and differentiation. Meta-analyses of exome-sequencing indicated that genes encoding subunits of SWI/SNF complexes are collectively mutated in ∼20% of cancers including ovarian cancer. Genomic and proteomic analyses indicate that SWI/SNF complex may play critical oncogenic roles during ovarian tumorigenesis by regulating the position of nucleosomes along DNA in ovarian tumor cells. In the proposed studies, we will characterize the molecular and cellular functions of the SWI/SNF complex in ovarian cancer. The therapeutic potentials by targeting the SWI/SNF complex will also be evaluated in the preclinical models of ovarian cancer. Our proposed studies will provide new insight into ovarian cancer epigenome and its therapeutic potentials.
Dr. Xiaowen Hu is currently a research resistant professor in Department of Obstetrics and Gynecology at University of Pennsylvania. Dr. Hu got her B.S. degree in biology from Sichuan University, China and received her Ph.D. from Shanghai Institutes for Biological Sciences of Chinese Academy of Sciences. Dr. Hu focused on the field of ovarian cancer research since she was a Ph.D. student. During her postdoc training at the Ovarian Cancer Research Center of University of Pennsylvania, Dr. Hu started exploring the genomics, epigenetics and no-coding genome of ovarian cancer. Her current research interest largely focused on the integration of cancer genome, epigenome, and computational biology, and then developing targeted therapy for ovarian cancer, especially, targeting the epigenetic modulators that significantly altered during ovarian cancer development and progression. Dr. Hu’s research has been supported by the Foundation for Women’s Cancer and Ovarian Cancer Research Fund Alliance. She is a previous recipient of Ann and Sol Schreiber Mentored Investigator Award from the Ovarian Cancer Research Fund.