Abstract 7545: Epigenetic plasticity in rewiring DNMT1/UHRF1-RB1- NFkB signaling circuit regulates asbestos-induced mesothelial malignant transformation

Abstract The exact mechanisms underlying the causal relationship between asbestos exposure and malignant mesothelioma (MM) have yet to be elucidated. Widespread genomic and epigenomic alterations are being implicated in rewiring of oncogenic signaling networks which may contribute to initiation and progression of MM. In the present study, we examined the molecular profiles of mesothelial cells exposed to asbestos in-vitro and found that asbestos-induced activation of DNMT1/UHRF1 mediated epigenetic repression of RB1 in normal mesothelial cells as well as mesothelioma cells via promoter-specific methylation mechanisms. RB1, as a noncanonical transcription factor, was capable of also negatively modulating the transcriptional activities of DNMT1/UHRF1 mesothelium and mesothelioma. Functioning as one of the downstream effectors of RB1, NFkB was also involved in the transcriptional regulation of DNMT1/UHRF1 directly in a promoter-selective manner and played a pivotal role in the acute as well as chronic functional and phenotypic changes of mesothelial cells following asbestos exposure. Pharmacological interference of the dysregulated RB1-DNMT1/UHRF1- RB1-NFkB signaling circuit constitutively arrested the invasive growth of MPM cells. In-vivo studies using FVB genetic background wild-type and Bap1+/- mice further revealed involvement of epigenetically dysregulation of the RB1-DNMT1/UHRF1- RB1-NFkB signaling circuit during asbestos-induced malignant transformation of mesothelial cells. Taken together, our data are the first to describe that asbestos epigenetically rewires the RB1-DNMT1/UHRF1- RB1-NFkB signaling circuit during mesothelioma development and suggest potential novel strategies to reverse these epigenetic perturbations for MPM treatment in the clinic. Citation Format: Sichuan Xi, Xinwei Wu, David M Straughan, Eden C Payabyab, Haitao Wang, Ruihong Wang, Mary Zhang, Shamus R. Carr, Chuong D. Hoang, David S. Schrump. Epigenetic plasticity in rewiring DNMT1/UHRF1-RB1- NFkB signaling circuit regulates asbestos-induced mesothelial malignant transformation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7545.