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

Achuth Padmanabhan (), Nicholes Candelaria, Kwong-Kwok Wong, Bryan C. Nikolai, David M. Lonard, Bert W. O’Malley and JoAnne S. Richards
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Achuth Padmanabhan: Baylor College of Medicine
Nicholes Candelaria: Baylor College of Medicine
Kwong-Kwok Wong: The University of Texas MD Anderson Cancer Center
Bryan C. Nikolai: Baylor College of Medicine
David M. Lonard: Baylor College of Medicine
Bert W. O’Malley: Baylor College of Medicine
JoAnne S. Richards: Baylor College of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-03599-w

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