Nuclear proteomic profiling of ovarian cancers with shared genomic alterations in SWI/SNF subunits
Ovarian Cancer (OvCa) is the most fatal gynecological malignancy, with poor prognosis at advanced stages (30%, 5y survival). Reliance on standard-of-care chemotherapies and absence of targeted therapies severely impact patient quality of life. Genomic profiling has identified that the tumor suppressor chromatin remodeling protein complex, SWI/SNF, is frequently mutated in OvCa. Specifically, the ARID1A and SMARCA4 subunits of the SWI/SNF complex are highly mutated in four of the OvCa subtypes: small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), endometrioid carcinoma, high grade serous ovarian cancer and clear cell carcinoma of the ovary. Our earlier large scale protein-protein interaction study has characterized the interactome of a residual SWI/SNF complex in SMARCA4 mutant SCCOHT cell lines. We hypothesize that distinct OvCa subtypes with similar mutations in SWI/SNF subunits share aberrant transcription factor landscape driven by atypical chromatin remodeling activity of residual SWI/SNF complex. To test this hypothesis, we profiled the nuclear proteome of seven SMARCA4- or ARID1A- mutant cell lines from four distinct OvCa subtypes. Irrespective of OvCa subtype, both SMARCA- and ARID1A- mutant cell lines show a downregulation of targets of transcription factor family E2F and an upregulation of targets of transcription factor family SRF, indicating lack of transcriptional repression of genes involved in proliferation. Further integration of nuclear proteomics with nuclear phosphoproteomics could identify common signaling mechanisms involved across multiple OvCa subtypes and inform novel therapeutic strategies.
