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

Abstract

// Kamil Lisek 1, 4 , Elena Campaner 1, 2 , Yari Ciani 1 , Dawid Walerych 1, 3 and Giannino Del Sal 1, 2 1 National Laboratory CIB, Area Science Park Padriciano, Trieste 34149, Italy 2 Department of Life Sciences, University of Trieste, Trieste 34127, Italy 3 Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw 02-106, Poland 4 Present address: Max-Delbrück-Centrum for Molecular Medicine, Berlin 13092, Germany Correspondence to: Giannino Del Sal, email: gdelsal@units.it Dawid Walerych, email: dwalerych@imdik.pan.pl Keywords: NRF2; mutant p53; cancer; oxidative stress Received: August 20, 2017     Accepted: March 09, 2018     Published: April 17, 2018 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.