Proteomic identification of ERP29 as a key chemoresistant factor activated by the aggregating p53 mutant Arg282Trp

• Published in: Oncogene Vol. 36; no. 39; pp. 5473 - 5483
• Main Authors: Zhang, Y, Hu, Y, Wang, J-L, Yao, H, Wang, H, Liang, L, Li, C, Shi, H, Chen, Y, Fang, J-Y, Xu, J
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.09.2017; Nature Publishing Group
• Subjects: 631/337/572; 631/67/395; 82/16; 82/58; 82/80; Amyloid; Analysis; Animals; Apoptosis; Cancer; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Care and treatment; Cell Biology; Cell cycle; Cell Line, Tumor; Chemoresistance; Chemotherapy; Chromatin; Cisplatin; Cisplatin - pharmacology; Diagnosis; Drug resistance; Drug Resistance, Neoplasm; Endoplasmic reticulum; Gene expression; Gene mutation; Genes; Genes, p53; Genomes; Heat-Shock Proteins - genetics; Human Genetics; Humans; Immunoprecipitation; Internal Medicine; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Male; Mass spectroscopy; Medicine; Medicine & Public Health; Mice; Mice, Inbred C57BL; Mice, Knockout; mRNA; Mutants; Mutation; Oncology; original-article; p53 Protein; Peptides; Protein folding; Proteins; Proteomics; Tumor Suppressor Protein p53 - genetics
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2017.152

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 R282W 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.