Abstract B24: Regulation of mutant p53 stability by the mevalonate pathway-Hsp40-CHIP axis

Abstract

Abstract Missense mutations in the p53 gene result in accumulation of dysfunctional p53 proteins in tumors with oncogenic gain-of-function activities, such as metastasis and chemotherapy resistance. Increasing evidence indicates that stabilization of mutant p53 (mutp53) in tumors is crucial for its oncogenic activities, while its knockdown reduces malignant progression. Thus, malignant properties of cancer cells are dependent on the presence of mutp53, providing a rationale to identify compounds that deplete mutp53 with minimal effects on wild-type p53 (wtp53). Toward this goal, we performed luciferase assay-based high-throughput screening of ~9,000 chemical compounds using cells expressing a chimeric fusion protein of p53R175H and a luciferase reporter. This screening led us to identify statins, a class of cholesterol-lowering drugs, as degradation inducers of conformational p53 mutants. Interestingly, statins showed minimal effects on wtp53 and DNA contact mutants. Moreover, CHIP ubiquitin ligase, but not MDM2, mediated statin-induced nuclear export, ubiquitination, and degradation of mutp53. Surprisingly, degradation of mutp53 by statins was independent of protein prenylation/lipidation or cholesterol synthesis, and specific reduction of mevalonte-5-phosphate (MVP) triggered mutp53 degradation. We also demonstrated that downregulation of a molecular chaperone Hsp40/DNAJA1 mirrored statin's effects on mutp53, while its overexpression nullified them. Moreover, statin-induced reduction of MVP inhibited the DNAJA1-mutp53 interaction. Biologically, statins preferentially suppressed malignant properties of mutp53-expressing cancer cells in vitro and in vivo. Our study proposes a novel role of DNAJA1 in inhibiting CHIP-mediated degradation of mutp53 induced by statins and highlights the significance of p53 status in impacting the efficacy of statins in cancer therapy and of DNAJA1 as a viable target for inducing mutp53 degradation. Citation Format: Alejandro Parrales, Atul Ranjan, Swathi V. Iyer, Scott Weir, Anuradha Roy, Tomoo Iwakuma. Regulation of mutant p53 stability by the mevalonate pathway-Hsp40-CHIP axis. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr B24.