Journal
NATURE CELL BIOLOGY
Volume 18, Issue 8, Pages 897-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb3380
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Funding
- European Research Council (ERC)
- Italian Health Ministry
- Italian Association for Cancer Research (AIRC)
- Italian Association for Cancer Research (AIRC) Special Program Molecular Clinical Oncology '5 per mille' [10016]
- Italian Ministry of Health [RF-2011-02346976]
- AIRC/FIRC fellowship
- Polish Academy of Sciences
- FEBS postdoctoral fellowship
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In cancer, the tumour suppressor gene TP53 undergoes frequent missense mutations that endow mutant p53 proteins with oncogenic properties. Until now, a universal mutant p53 gain-of-function program has not been defined. By means of multi-omics: proteome, DNA interactome (chromatin immunoprecipitation followed by sequencing) and transcriptome (RNA sequencing/microarray) analyses, we identified the proteasome machinery as a common target of p53 missense mutants. The mutant p53-proteasome axis globally affects protein homeostasis, inhibiting multiple tumour-suppressive pathways, including the anti-oncogenic KSRP-microRNA pathway. In cancer cells, p53 missense mutants cooperate with Nrf2 (NFE2L2) to activate proteasome gene transcription, resulting in resistance to the proteasome inhibitor carfilzomib. Combining the mutant p53-inactivating agent APR-246 (PRIMA-1MET) with the proteasome inhibitor carfilzomib is effective in overcoming chemoresistance in triple-negative breast cancer cells, creating a therapeutic opportunity for treatment of solid tumours and metastasis with mutant p53.
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