Abstract 1047: Suppression of the chromatin remodeling protein CHD3 and platinum resistance in ovarian cancer

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AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012






Epithelial ovarian cancer is the leading cause of death from gynecological malignancies. Currently platinum-based chemotherapy, coupled with a taxane based drug is the primary treatment for ovarian cancer. Approximately 25% of patients either present with or rapidly develop resistance to platinum based chemotherapy and all recurrent tumors ultimately become resistant. Epigenetic modifications have been associated with tumor formation and progression and may contribute to therapy response. We hypothesize that Epigenetic changes such as DNA CpG methylation is in part responsible for the onset of chemoresistance of EOC. To identify epigenetically regulated genes associated with ovarian cancer chemotherapy resistance, a genome wide approach was used. For the most significant genes an in vitro culture system was developed to study platinum resistance. Candidate genes were screened by addition of shRNAs to model the transcriptional suppression caused by DNA methylation and genes that scored positive for increasing resistance were identified, one of them being the CHD3 gene. Here we show that loss of expression of CHD3, a member of the Mi-2/NuRD complex, causes increased resistance to platinum chemotherapy drugs. Additionally, ovarian cell lines transcriptionally silenced for CHD3 are more invasive, and have increased migratory ability. Recent evidence suggests molecular and phenotypic associations between chemo resistance and the acquisition of epithelial-mesenchymal transition of cancer cells. The transition of epithelial cell to a mesenchymal cell requires an alteration in morphology, cellular architecture, adhesion, and migration capacity. Cancer cells undergoing EMT can acquire invasive properties and enter the surrounding stroma, resulting in the creation of a favorable microenvironment for cancer progression and metastasis. Our results indicate that when CHD3 is silenced, cells undergo an EMT-like transition thereby allowing them to bypass apoptosis and resist platinum based therapy. Taken together, we provide the first evidence of a role for CHD3 as an important epigenetic regulator of chemoresistance in ovarian cancer and hypothesize EMT as one of the underlying mechanisms. Furthermore, CHD3 expression might represent a therapy response predictor and could be a future therapeutic target for ovarian cancer.

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