Epigenetic Mechanisms of Biliary Epithelial Neoplasia

Tulane University Of Louisiana, New Orleans LA

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Abstract

Project Summary/Abstract Cholangiocarcinoma (CCA) is a highly malignant epithelial cancer of the hepatobiliary system with biliary differentiation. The incidence and mortality of CCA is rising worldwide and currently there is no effective chemoprevention or treatment. The molecular pathogenesis underlying biliary epithelial neoplasia involves genetic and epigenetic changes leading to alterations of oncogenic and tumor suppressive pathways. Studies with integrative genomics approaches have led to the identification of dysregulated transcriptomic landscapes in CCA. In parallel, compelling evidence has revealed that epigenetic alterations are also importantly implicated in the pathogenesis of human CCA. Our laboratory has been focused on the study of epigenetic mechanisms of CCA. This project centers on the mechanism of histone methylation in biliary carcinogenesis. Our experimental results during the prior grant period establish the importance of two key histone methyltransferases, EZH2 (enhancer of Zeste 2) and G9a/EHMT2 (euchromatic histone-lysine N- methyltransferase 2), in epigenetic regulation of CCA. Our findings have led us to develop the current renewal proposal which aims to further delineate the mechanism and interaction of these two crucial histone methyltransferases in CCA. EZH2 and G9a/EHMT2 are two major epigenetic silencing enzymes which methylate H3K27 and H3K9, respectively. Accumulating evidence suggests the existence of molecular crosstalk between EZH2 and G9a/EHMT2 epigenetic silencing mechanisms, although details of their cross interactions are not defined. Our new preliminary data reveal that the expression and interaction of EZH2 and G9a/EHMT2 in CCA cells are tightly controlled by RBM39 (RNA-binding motif protein 39), an RNA-binding protein essential for alternative RNA splicing. Based on our new preliminary data and published studies, we hypothesize that RBM39 is an important epigenetic regulator which controls cholangiocarcinogenesis though regulation of EZH2 and G9a/EHMT2. We postulate that RBM39-mediated regulation of EZH2 and G9a/EHMT2 and their cross interactions are crucial in CCA development and progression. Consequently, we hypothesize that inhibition of the RBM39-EZH2-G9a/EHMT2 epigenetic pathway will prevent CCA growth, and that this strategy may represent an effective therapeutic approach for CCA treatment. These hypotheses will be evaluated in two interrelated specific aims. Aim 1 is proposed to determine the effect and mechanism of the RBM39-EZH2- G9a/EHMT2 epigenetic pathway in biliary carcinogenesis. Studies will be carried out to delineate RBM39-regulated EZH2 and G9a/EHMT2 expression and their cross interactions in biliary epithelial and cancer cells. The impact of RBM39-EZH2-G9a/EHMT2 in CCA will be evaluated in complementary models of CCA development and progression. The goal of Aim 2 is to evaluate the therapeutic efficacy of inhibiting RBM39 for CCA treatment in preclinical models of CCA. The effect of RBM39 inhibition in combination with current chemotherapy and/or immunotherapy will be further assessed. Together, the proposed studies will define the role of the RBM39-EZH2- G9a/EHMT2 epigenetic pathway in biliary carcinogenesis and the findings will provide important implication for the development of new epigenetics-based target therapy for CCA treatment.