American Association for Cancer Research
00085472can203855-sup-255681_2_supp_7154335_q73l1m.pdf (6.64 MB)

Supplementary Data from Valosin-Containing Protein Stabilizes Mutant p53 to Promote Pancreatic Cancer Growth

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journal contribution
posted on 2023-03-31, 04:24 authored by Jieqiong Wang, Yajie Chen, Canhua Huang, Qian Hao, Shelya X. Zeng, Sara Omari, Yu Zhang, Xiang Zhou, Hua Lu

Wang et al suppl infor


Reynolds and Ryan Families Chair Fund of Translational Cancer



Approximately 80% of human pancreatic ductal adenocarcinomas (PDAC) harbor TP53 mutations, among which, R273H is the most frequent. Although p53-R273H is known to possess gain-of-function properties, how it is regulated in PDAC has not been extensively explored. Here we identify valosin-containing protein (VCP) as a regulator of p53-R273H by conducting immunoprecipitation-tandem mass spectrometry analysis. VCP bound p53-R273H at its DNA binding domain. Ectopic or endogenous VCP stabilized p53-R273H by binding to MDM2 and disrupting its association with mutant p53. Inhibition of VCP either by genetic depletion or the pharmacologic inhibitor CB-5083 increased ubiquitination and degradation of p53-R273H, leading to cell death. Consistently, ablation of VCP markedly retarded growth of cultured PDAC cells and xenograft PDAC tumors. Together, these results unveil VCP as a novel partner of p53-R273H in promoting PDAC growth and as a potential target for developing anti-PDAC therapy. These findings identify valosin-containing protein (VCP) as a novel regulator of p53-R273H stability and suggest VCP as a potential target for development of pancreatic cancer therapy.