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

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.

TIFAB Regulates USP15-Mediated p53 Signaling during Stressed and Malignant Hematopoiesis

“…Modulating either the level or the activity of USP enzymes is an effective approach to simultaneously alter the stability of downstream substrates. Therefore, understanding the regulation of both catalytically dependent and independent functions of USP15 will inform future studies on targeting USP15 with small-molecule inhibitors (Zhang et al, 2015;Padmanabhan et al, 2018).…”

USP15 deubiquitinase safeguards hematopoiesis and genome integrity in hematopoietic stem cells and leukemia cells

“…USP15 gene alterations have been found in cancer, in particular glioblastoma, breast, ovarian and recently in non-small cell lung cancer (Eichhorn et al, 2012;Fielding et al, 2018;Padmanabhan et al, 2018;Peng et al, 2019), as well as copy number losses in pancreatic cancer (Srihari and Ragan, 2013). Here, the analysis of cancer databases uncovers USP15 highest expression in primary blood-derived tumors and alterations in leukemia patients, particularly CML and AML.…”

WOMEN IN REPRODUCTIVE SCIENCE: Discovering science and the ovary: a career of joy

“…Thus, our current studies are focused on determining how specific GOF R175H, R273H and R248Q mutant p53 alleles impact the growth of ovarian cancer cells in the same Kras/Pten genetic background. We already know that the R175H p53 mutant protein behaves differently than the R273H and R248Q mutant p53 proteins in response to cytotoxic drugs and in tumor morphology (Padmanabhan et al 2018). Thus, we anticipate finding distinct mechanisms by which each of these regulates responses to steroids and the immune cell microenvironment.…”