Mutant p53 tunes the NRF2-dependent antioxidant response to support survival of cancer cells

Oncotarget
Kamil LisekGiannino Del Sal

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.

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Mar 21, 2019·Journal of Molecular Cell Biology·Sofi E ErikssonKlas G Wiman
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Datasets Mentioned

BETA
MDA-MB-231

Methods Mentioned

BETA
immunoprecipitation
co-immunoprecipitation
transfection
co-IP
ChIP
FCS
genotyping
Biosample
PCR
Protein Assay

Software Mentioned

FlowJo
plotter
CellROX
Bioconductor
Km
Leica Application Suite
GraphPad
R
R Core
PowerPlex 18D System

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