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Title:Role of Epigenetics in Testicular Cancer Cell Drug Response
Author(s):Yerby, Clifford J
Contributor(s):Spinella, Michael J (Undergraduate Faculty Advisor)
Department / Program:Comparative Biosciences
Degree Granting Institution:University of Illinois at Urbana
Degree:B.S. (bachelor's)
Subject(s):Testicular Germ Cell Tumors (TGCTs)
Chemotherapeutic Resistance
Abstract:Testicular cancer is highly curable with the chemotherapeutic cisplatin. However, 15-20% of patients are resistant and succumb to their disease. Previously we showed that cisplatin refractory testicular cancer is highly sensitive to the DNA methyltransferase inhibitor, 5-aza deoxycytidine (5-aza). The mechanisms for cisplatin sensitivity and resistance in testicular cancer is unclear. If we can understand why testicular cancer is so curable, this knowledge could be applied to other cancer types. To better understand the mechanism of chemotherapy sensitivity and resistance in testicular cancer cells our lab generated two series of cell models, one resistant to cisplatin and the other resistant to 5- aza. We noted a reciprocal relationship between cisplatin and 5-aza resistance, with cisplatin resistance associated with increased sensitivity to 5-aza and 5-aza resistance associated with increased sensitivity to cisplatin. Transcriptomics revealed downregulation of the H3K27me3-mediated polycomb pathway in cisplatin resistant cells and upregulation of this pathway with 5-Aza resistance. To explore possible mechanisms for this reciprocal epigenetic modeling, the expression of the gene family responsible for histone lysine demethylation, the KDM family, was assessed by qPCR. Many KDM genes, including those responsible for H3K27me3 demethylation, were upregulated in cisplatin resistant cells and downregulated in 5-Aza resistant cells. Changes in KDM gene expression could explain, in part, globally altered levels of H3K27 methylation. We are performing genetic and pharmacologic studies to further validate a role for the H3K27me3 polycomb pathway in chemotherapeutic resistance, with the goal of devising novel therapies for testicular and potentially other cancers.
Issue Date:2021
Genre:Dissertation / Thesis
Rights Information:Copyright 2020 Clifford Yerby
Date Available in IDEALS:2021-05-10

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