Ironing Out Roles and Regulation of NRF2 in a Hereditary Cancer Syndrome

Abstract

The deadly kidney cancers associated with hereditary leiomyomatosis and renal cell cancer (HLRCC) show activation of the nuclear factor (erythroid 2)-like 2 (NFE2L2, NRF2) transcription factor. NRF2 activation causes chemoresistance and limits therapeutic efficacy. However, clear mechanisms of how NRF2 activation in HLRCC contributes to the progression of the disease are not known, and no treatments have been identified to circumvent the NRF2-mediated chemoresistance in HLRCC. This dissertation explores the roles of NRF2 in cancer, particularly HLRCC. Here, we provide a comprehensive catalog of NRF2 mutations across all tumor types, and characterize underappreciated NRF2-R34 mutations that activate the antioxidant response. We then focus on a particular cancer harboring NRF2 activation, HLRCC, and provide the first evidence of a role for NRF2 in upregulating the iron storage protein, ferritin, to induce a chronic proliferative signal in HLRCC. To circumvent the known therapeutic resistance of HLRCC, we demonstrate that HLRCC is sensitive to an iron-dependent cell death, ferroptosis. Lastly, to further characterize the NRF2 regulatory network, we systematically identify previously-unrecognized negative regulators of NRF2. This dissertation presents mechanistic insight into the iron-dependent role of NRF2 in cancer, particularly HLRCC, while simultaneously identifying new regulators for NRF2 and new treatment modalities for HLRCC.