title: Proteasome machinery is instrumental in a common gain-of-function program of the p53 missense mutants in cancer.
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.
authors.affiliation: Laboratorio Nazionale CIB, Area Science Park Padriciano, Trieste 34149, Italy.
authors.forename: Dawid
authors.initials: D
authors.lastname: Walerych
authors.affiliation: Laboratorio Nazionale CIB, Area Science Park Padriciano, Trieste 34149, Italy.|Dipartimento di Scienze della Vita-Università degli Studi di Trieste, Trieste 34127, Italy.
authors.forename: Kamil
authors.initials: K
authors.lastname: Lisek
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova 35128, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Sommaggio
authors.affiliation: Laboratorio Nazionale CIB, Area Science Park Padriciano, Trieste 34149, Italy.
authors.forename: Silvano
authors.initials: S
authors.lastname: Piazza
authors.affiliation: Laboratorio Nazionale CIB, Area Science Park Padriciano, Trieste 34149, Italy.
authors.forename: Yari
authors.initials: Y
authors.lastname: Ciani
authors.affiliation: Laboratorio Nazionale CIB, Area Science Park Padriciano, Trieste 34149, Italy.
authors.forename: Emiliano
authors.initials: E
authors.lastname: Dalla
authors.affiliation: Laboratorio Nazionale CIB, Area Science Park Padriciano, Trieste 34149, Italy.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Rajkowska
authors.affiliation: Laboratorio Nazionale CIB, Area Science Park Padriciano, Trieste 34149, Italy.|Laboratory of Neurogenetics, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw 02106, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Gaweda-Walerych
authors.affiliation: Laboratorio Nazionale CIB, Area Science Park Padriciano, Trieste 34149, Italy.|Dipartimento di Scienze della Vita-Università degli Studi di Trieste, Trieste 34127, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Ingallina
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (IEO), Milan 20141, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Tonelli
authors.affiliation: Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Milan 20139, Italy.
authors.forename: Marco J
authors.initials: MJ
authors.lastname: Morelli
authors.affiliation: Laboratory of Experimental Oncology and Pharmacogenomics, IRCCS 'Salvatore Maugeri' Foundation, Pavia 27100, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Amato
authors.affiliation: Laboratory of Experimental Oncology and Pharmacogenomics, IRCCS 'Salvatore Maugeri' Foundation, Pavia 27100, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Eterno
authors.affiliation: Laboratory of Experimental Oncology and Pharmacogenomics, IRCCS 'Salvatore Maugeri' Foundation, Pavia 27100, Italy.|Unit of Medical Oncology, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo 24127, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Zambelli
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova 35128, Italy.|Istituto Oncologico Veneto IOV-IRCCS, Padova 35128, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Rosato
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (IEO), Milan 20141, Italy.|Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Milan 20139, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Amati
authors.affiliation: Biochemical Proteomics Group, Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried D82152, Germany.
authors.forename: Jacek R
authors.initials: JR
authors.lastname: Wiśniewski
authors.affiliation: Laboratorio Nazionale CIB, Area Science Park Padriciano, Trieste 34149, Italy.|Dipartimento di Scienze della Vita-Università degli Studi di Trieste, Trieste 34127, Italy.
authors.forename: Giannino
authors.initials: G
authors.lastname: Del Sal
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics; D050505:Mutant Proteins / Q000187:drug effects* / Q000235:genetics; D020125:Mutation, Missense / Q000187:drug effects* / Q000235:genetics; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000235:genetics; D009842:Oligopeptides / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects* / Q000235:genetics; D020543:Proteome / Q000187:drug effects; D011812:Quinuclidines / Q000494:pharmacology; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D035683:MicroRNAs; D050505:Mutant Proteins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D009842:Oligopeptides; D020543:Proteome; D011812:Quinuclidines; D016159:Tumor Suppressor Protein p53; C524865:carfilzomib; D046988:Proteasome Endopeptidase Complex; C533410:eprenetapopt