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.

Emerging therapeutic targets in myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas

“…A recent study analyzed the impact of TP53* in MPN patients and, although it is common that at least one somatic TP53* allele is transcribed in patient cells, the authors did not find a direct association between TP53 inactivation and HU resistance or blast transformation [33]. TP53 can also interact with STAT3 and STAT5 [39,40] and it induces mRNA expression of STAT5A , but not of STAT5B [41]. Overall, current sequencing data suggest that the age of patients is the strongest factor affecting low-burden TP53* incidence in MPN, which may persist for years without an immediate risk of progression.…”

Multi-omics reveals global effects of mutant p53 gain-of-function

“…In contrast, the common and the proteasome subunit gene signatures, containing transcripts shared by the mutant p53 program in 5 cell lines, prognosed the bad outcome more efficiently. 2 This indicates that missense p53 mutants largely share the most significant downstream oncogenic program.…”

“…It became apparent that the mutant p53-dependent upregulation of cell's protein levels is indeed directly linked to the mutant p53's role as a potent transcriptional activator, while the mutant p53-dependent downregulation of proteins is mostly controlled post-transcriptionally, through the proteasome machinery. 2 Of note, the downstream effects of the mutant p53-Nrf2-proteasome axis include destabilization of the antioncogenic KSRP protein -a component of Dicer and Drosha miRNA processing complexes, responsible for maturation of a subset of oncosuppressive miRNAs. 2 To our knowledge, this is the first indication of a direct link between elevated proteasome activity and alteration of miRNA homeostasis relevant for carcinogenesis.…”

“…2 Of note, the downstream effects of the mutant p53-Nrf2-proteasome axis include destabilization of the antioncogenic KSRP protein -a component of Dicer and Drosha miRNA processing complexes, responsible for maturation of a subset of oncosuppressive miRNAs. 2 To our knowledge, this is the first indication of a direct link between elevated proteasome activity and alteration of miRNA homeostasis relevant for carcinogenesis. Together with a recent study by Garibaldi and coworkers showing that mutant p53 inhibits Drosha/Microprocessor complex, 3 and earlier studies on mutant p53 influence on Dicer and Drosha, 4,5 our results demonstrate that mutant p53 has a profound global effect on cellular miRNA processing via several overlapping routes.…”

“…Zhu et al noticed that mutant p53 cells are sensitized to COMPASS methyltransferase complex inhibitors in vitro, 6 while we found that mutant p53 induces resistance to proteasome inhibitors (such as carfilzomib), which can be overcome in TNBC xenografts by targeting of mutant p53 by APR-246 (PRIMA-1MET). 2 Now these approaches, that could provide simple therapeutic strategies to target a large number of tumors bearing different mutant p53 proteins, need to be progressed toward the clinical tests.…”