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 R282WTP53-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.
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This project was supported by grants from National Natural Science Foundation of China (81572326, 81322036, 81272383, 81421001, 81320108024, 81530072, 81602518, 81502015 and 81572303); Top-Notch Young Talents Program of China (ZTZ2015–48); Shanghai Municipal Education Commission–Gaofeng Clinical Medicine Grant Support (20152514); National Key Research & Development (R&D) Plan (2016YFC0906000 and 2016YFC0906002); and National Key Technology Support Program (2015BAI13B07). The sponsors of this study had no role in the collection of the data, the analysis and interpretation of the data, the decision to submit the manuscript for publication or the writing of the manuscript.
YZ and JX wrote the manuscript. YZ, YH, J-LW, HY, HW, LL, CL, HS, YC and J-YF performed experiments and/or analyzed the results.
The authors declare no conflict of interest.
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Zhang, Y., Hu, Y., Wang, J. et al. Proteomic identification of ERP29 as a key chemoresistant factor activated by the aggregating p53 mutant Arg282Trp. Oncogene 36, 5473–5483 (2017) doi:10.1038/onc.2017.152
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