USP15-dependent lysosomal pathway controls p53-R175H turnover in ovarian cancer cells

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Abstract

Gain-of-function p53 mutants such as p53-R175H form stable aggregates that accumulate in cells and play important roles in cancer progression. Selective degradation of gain-of-function p53 mutants has emerged as a highly attractive therapeutic strategy to target cancer cells harboring specific p53 mutations. We identified a small molecule called MCB-613 to cause rapid ubiquitination, nuclear export, and degradation of p53-R175H through a lysosome-mediated pathway, leading to catastrophic cancer cell death. In contrast to its effect on the p53-R175H mutant, MCB-613 causes slight stabilization of p53-WT and has weaker effects on other p53 gain-of-function mutants. Using state-of-the-art genetic and chemical approaches, we identified the deubiquitinase USP15 as the mediator of MCB-613's effect on p53-R175H, and established USP15 as a selective upstream regulator of p53-R175H in ovarian cancer cells. These results confirm that distinct pathways regulate the turnover of p53-WT and the different p53 mutants and open new opportunities to selectively target them.

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Padmanabhan, A., Candelaria, N., Wong, K. K., Nikolai, B. C., Lonard, D. M., O’Malley, B. W., & Richards, J. S. (2018). USP15-dependent lysosomal pathway controls p53-R175H turnover in ovarian cancer cells. Nature Communications, 9(1). https://doi.org/10.1038/s41467-018-03599-w

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