Type
Text
Type
Dissertation
Advisor
Robert Lucito. | Linda VanAelst | Wei-Xing Zong | Stefan Tafrov | Nevenka Dimitrova.
Date
2011-08-01
Keywords
Genetics | cancer, chemotherapy, methylation
Department
Department of Genetics
Language
en_US
Source
This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree.
Identifier
http://hdl.handle.net/11401/70811
Publisher
The Graduate School, Stony Brook University: Stony Brook, NY.
Format
application/pdf
Abstract
Epithelial ovarian cancer is the leading cause of death from gynecological malignancies. Currently platinum-based chemotherapy (such as cisplatin or carboplatin), coupled with a taxane based drug such as paclitaxel 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 are resistant. Epigenetic modifications have been associated with tumor formation and progression and may contribute to therapy response. We have screened a number of genes and family members for methylation difference between resistant patients and sensitive patients, and had shown that CHD3 is silenced through an epigenetic mechanism in both ovarian cancer cell lines and primary ovarian tumors. Here we show that for CHD3, a member of the Mi-2 NuRD complex, that loss of expression causes increased resistance to the chemotherapy drugs Carboplatin and Cisplatin. Additionally, cell lines transcriptionally silenced for CHD3 are more invasive, have migratory ability, and display a transformed epithelial to mesenchymal (EMT) phenotype. Cells display a striking decrease in growth, not caused by apoptosis or senescence. 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 might represent a response predictor. Based on these findings we propose that CHD3 will be a future therapeutic target for ovarian cancer.
Recommended Citation
Cutter, Noelle L., "A role for the chromatin remodeler CHD3 in epithelial ovarian cancer platinum resistance" (2011). Stony Brook Theses and Dissertations Collection, 2006-2020 (closed to submissions). 30.
https://commons.library.stonybrook.edu/stony-brook-theses-and-dissertations-collection/30