Abstract 391: Role of NRF2 in HIF-2α-mediated cancer stem cell phenotype

Abstract The acquisition of cancer stem cell (CSC) properties is influenced by the microenvironment, with tumor hypoxia playing a pivotal role. Elevated levels of nuclear factor erythroid 2-like 2 (NRF2), a redox balance-maintaining transcription factor, have been linked to enhanced tumor growth and therapy resistance. This study investigates the potential role of NRF2 in hypoxia-inducible factor-2α (HIF-2α) regulation in cancers. First, in a model of a 72-hour hypoxic incubation, chronic hypoxia led to CSC characteristics, including increased expression of KLF4 and OCT4, heightened cancer migration, and spheroid growth, which are associated with HIF-2α accumulation. NRF2 inhibition mitigated these effects, while NRF2 activation enhanced chronic hypoxia-induced CSC traits. Mechanistically, NRF2/miR181a-2 signaling emerged as a regulator of HIF-2α-mediated CSC phenotypes in chronic hypoxic conditions. Second, in clear cell renal cell carcinoma (ccRCC), characterized by pVHL gene mutation and constitutive HIF-2α elevation, the role of NRF2 in aggressive cancer phenotypes was explored. Silencing of NRF2 impaired aggressive phenotypes in multiple ccRCC cell lines with a reduction in HIF-2α expression. Promoter analysis elucidated that NRF2 directly upregulates HIF-2α expression through antioxidant response elements in the human HIF-2α gene. Collectively, our study suggests the involvement of NRF2/miR181a-2 signaling in the development of HIF-2α-mediated CSC phenotypes in sustained hypoxic environments and also proposes NRF2 as a promising target for mitigating HIF-2α-mediated CSC traits in ccRCC. Citation Format: Mi-Kyoung Kwak, Steffanus P. Hallis. Role of NRF2 in HIF-2α-mediated cancer stem cell phenotype [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 391.