Proteasome machinery is instrumental in a common gain-of-function program of the p53 missense mutants in cancer

• Published in: Nature cell biology Vol. 18; no. 8; pp. 897 - 909
• Main Authors: Walerych, Dawid, Lisek, Kamil, Sommaggio, Roberta, Piazza, Silvano, Ciani, Yari, Dalla, Emiliano, Rajkowska, Katarzyna, Gaweda-Walerych, Katarzyna, Ingallina, Eleonora, Tonelli, Claudia, Morelli, Marco J., Amato, Angela, Eterno, Vincenzo, Zambelli, Alberto, Rosato, Antonio, Amati, Bruno, Wiśniewski, Jacek R., Del Sal, Giannino
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2016; Nature Publishing Group
• Subjects: 13/89; 38/61; 38/91; 45/77; 49/15; 631/67; 631/80/474/2085; 64/60; 82/51; 82/58; Animals; Antineoplastic Agents - pharmacology; Binding sites; Breast cancer; Cancer; Cancer Research; Care and treatment; Cell Biology; Developmental Biology; Gene expression; Gene mutations; Health aspects; Humans; Life Sciences; Mice; MicroRNAs - genetics; Mutant Proteins - drug effects; Mutant Proteins - genetics; Mutation; Mutation, Missense - drug effects; Mutation, Missense - genetics; Neoplasm Metastasis - drug therapy; Neoplasm Metastasis - genetics; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Oligopeptides - pharmacology; Oncology; Properties; Proteasome Endopeptidase Complex - drug effects; Proteasome Endopeptidase Complex - genetics; Proteins; Proteome - drug effects; Proteomics; Quinuclidines - pharmacology; Signal transduction; Stem Cells; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - genetics; Tumor suppressor genes; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Italy
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/ncb3380

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. Walerych  et al.  show that p53 missense mutants upregulate the proteasome and increase breast cancer cell resistance to proteasome inhibitors. Combined inhibition of p53 mutants and the proteasome leads to increased therapeutic efficacy.