Mutation of the TP53 gene represents a prevalent genetic alteration in human cancers, and a subset of p53 mutants may form amyloid-like aggregates that contribute to the gain of oncogenic functions (GOFs) and chemoresistance. Here we identify the pathways that may mediate the aggregation-associated GOF by using combined proteomic analysis and genome-wide recruitment profiling. Mass spectrometry revealed activation of unfolded protein response (UPR) pathway and upregulation of endoplasmic reticulum protein 29 (ERp29) in TP53-expressing cells that were exposed to cisplatin stress. Chromatin immunoprecipitation sequencing identified a significant 'CCCASS' binding motif of Arg282Trp, which is present in the promoter region of ERP29 gene. The mutant p53 upregulated ERP29 mRNA and protein expression levels, whereas targeting ERP29 by specific small interfering RNAs suppressed the chemoresistant effect of Arg282Trp. The anti-aggregation peptide ReACp53 significantly decreased ERP29 expression and suppressed the chemoresistant effect. These findings highlight a role of ERP29 in the acquired chemoresistance of cancer cells expressing the aggregating p53 mutant Arg282Trp. Our results also suggest that ERP29-mediated GOF can be targeted by the anti-aggregation peptide ReACp53.

The frequency of p53 mutations in colorectal cancer (CRC) is approximately 40–50%. A variety of therapies are being developed to target tumors expressing mutant p53. However, potential therapeutic targets for CRC expressing wild‐type p53 are rare. In this study, we show that METTL14 is transcriptionally activated by wild‐type p53 and suppresses tumor growth only in p53‐wild‐type (p53‐WT) CRC cells. METTL14 deletion promotes both AOM/DSS and AOM‐induced CRC growth in mouse models with the intestinal epithelial cell‐specific knockout of METTL14. Additionally, METTL14 restrains aerobic glycolysis in p53‐WT CRC, by repressing SLC2A3 and PGAM1 expression via selectively promoting m6A‐YTHDF2‐dependent pri‐miR‐6769b/pri‐miR‐499a processing. Biosynthetic mature miR‐6769b‐3p and miR‐499a‐3p decrease SLC2A3 and PGAM1 levels, respectively, and suppress malignant phenotypes. Clinically, METTL14 only acts as a beneficial prognosis factor for the overall survival of p53‐WT CRC patients. These results uncover a new mechanism for METTL14 inactivation in tumors and, most importantly, reveal that the activation of METTL14 is a critical mechanism for p53‐dependent cancer growth inhibition, which could be targeted for therapy in p53‐WT CRC.