Abstract 1455: NANOG binds polycomb repressive complex 2 to reprogram metabolism to promote slow cycling phenotype in experimental mouse and clinical carcinoma

Abstract

Abstract Pluripotency transcription factor NANOG represses mitochondrial oxidative phosphorylation (OXPHOS) genes, but activates fatty acid oxidation (FAO) to support self-renewal and drug resistance of tumor-initiating stem-like cells (TICs). Hepatoceullular carcinomas (HCCs: 39%) associated with HCV and alcohol have mutations in ARID1A, a component of the chromatin remodeling complex SWI/SNF. We hypothesized that NANOG binds polycomb repressive complex 2 (PRC2) to reprogram metabolism to promote slow cycling phenotype. Here, the Genome-scale CRISPR Knock-Out (GeCKO) screening with ARID1A mutation identified PRC2 complex genes (EZH2, SUZ12 and EED) in patient-derived TICs. NANOG together with the PRC2 complex inhibits OXPHOS to generate TICs with label-retaining ability and therapy resistance. NANOG binds PRC2 complex. ARID1A gene loss promotes sorafenib-resistance phenotype and self-renewal through PRC2 complex genes. ARID1A mutation promoted HCC development in humanized FRG mice with HCCs. The studies established a novel therapy to overcome the chemoresistance of TICs for HCC treatment. Citation Format: Da-Wei Yeh, Juan Carlos Hernandez, Keigo Machida. NANOG binds polycomb repressive complex 2 to reprogram metabolism to promote slow cycling phenotype in experimental mouse and clinical carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1455.