Abstract
NRF2 (NFE2L2) is one of the main regulators of the antioxidant response of the cell. Here we show that in cancer cells NRF2 targets are selectively upregulated or repressed through a mutant p53-dependent mechanism. Mechanistically, mutant p53 interacts with NRF2, increases its nuclear presence and resides with NRF2 on selected ARE containing gene promoters activating the transcription of a specific set of genes while leading to the transcriptional repression of others. We show that thioredoxin (TXN) is a mutant p53-activated NRF2 target with pro-survival and pro-migratory functions in breast cancer cells under oxidative stress, while heme oxygenase 1 (HMOX1) is a mutant p53-repressed target displaying opposite effects. A gene signature of NRF2 targets activated by mutant p53 shows a significant association with bad overall prognosis and with mutant p53 status in breast cancer patients. Concomitant inhibition of thioredoxin system with Auranofin and of mutant p53 with APR-246 synergizes in killing cancer cells expressing p53 gain-of-function mutants.
Highlights
The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) is the main and evolutionary conserved regulator of the antioxidant pathways in the cell
In order to evaluate the impact of mutant p53 on the expression of NRF2 transcriptional program, we perused already available datasets to sort out a signature consisting of well established NRF2 target genes which represent various biological processes important for normal and cancer cell metabolism
We compared the expression of selected NRF2 target genes between normal breast epithelial MCF10A cells bearing wild-type p53, MCF10A cells silenced for TP53 (MCF10A+shTP53) and MCF10A cells silenced for wild-type TP53, ectopically overexpressing the oncogenic mutant p53 R280K (MCF10A+mtp53 R280K)
Summary
The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) is the main and evolutionary conserved regulator of the antioxidant pathways in the cell. Various oncogenes have been reported to impact the NRF2 pathway by upregulating total mRNA and protein levels of NRF2 [4, 5]. NRF2 controls key components of endogenous antioxidant systems in both cancer and normal cells [1, 6]. Until now over 500 genes have been reported to be under NRF2 control [7]. While in normal cells the NRF2/Keap antioxidant pathway plays a crucial role in maintaining cellular homeostasis and preventing tumorigenesis [1], in cancer cells high expression of NRF2-regulated genes provides them with cytoprotection, contributing to their oncogenic capabilities [8, 9]
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