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EnglishIn 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.
| Titolo: | Proteasome machinery is instrumental in a common gain-of-function program of the p53 missense mutants in cancer | |
| Autori: | ||
| Data di pubblicazione: | 2016 | |
| Stato di pubblicazione: | Pubblicato | |
| Rivista: | ||
| Abstract: | 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. | |
| Handle: | http://hdl.handle.net/11368/2919896 | |
| Digital Object Identifier (DOI): | http://dx.doi.org/10.1038/ncb3380 | |
| URL: | https://www.nature.com/articles/ncb3380 | |
| Appare nelle tipologie: | 1.1 Articolo in Rivista |
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| File | Descrizione | Tipologia | Licenza | |
|---|---|---|---|---|
| ncb3380-s1suppl.inf.2.pdf | Supplementary Information | Documento in Versione Editoriale | Copyright Editore | Administrator Richiedi una copia |
| nature.pdf | Documento in Versione Editoriale | Copyright Editore | Administrator Richiedi una copia |
