Abstract 807: HDAC1 -dependent epigenetic loss of ATP5H confers a stem cell-like phenotype with features associated with metastatic capacity through mitochondrial reprogramming

Abstract

Abstract The failure of most cancer therapies is the emergence of tumor cells that are refractory to available agent. Here we report that single-modality cancer therapy triggers broad-spectrum cross-resistance to multiple clinical interventions. This multi-modality resistance arises through a core metabolic reprogramming pathway instigated by loss of the ATP synthase subunit ATP5H, which sequentially leads to accumulation of reactive oxygen species and stabilization of HIF-1α under normoxia. Furthermore, we found that NANOG/HDAC1 axis regulates epigenetic loss of ATP5H, this pathway confers tumor cells a stem cell-like phenotype with features associated with metastatic capacity. ATP5H loss in the tumor is strongly linked to failure of therapy, and poor survival in cancer patients. Integration of these biological features provides the best basis for understanding patient outcome in this setting and suggests that loss of ATP5H shapes the tumor resistance to multiple anti-tumor therapy. Citation Format: Suyeon Kim, Kwon-Ho Song, Tae-Woo Kim. HDAC1 -dependent epigenetic loss of ATP5H confers a stem cell-like phenotype with features associated with metastatic capacity through mitochondrial reprogramming [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 807.