Fig. 7

USP15 depletion causes cancer cell death in ovarian cancer cells expressing p53-R175H. a p53 knockdown causes decreased viability in ovarian cancer cells expressing GOF mutp53, but not p53-WT and p53-null cells. Values are normalized mean ± s.e.m. (n = 3; *p-value < 0.05). b Ovarian cancer cells expressing p53-R175H (TYK-Nu and TOV-112D) are more sensitive to MCB-613 than ALST (p53-WT), OVCA420 (p53-R273H), and COV362 (p53-Y220C). Values are normalized mean ± s.e.m. (n = 3). c TYK-Nu cells are more sensitive to PR-619 compared with ALST and OVCA420 cells. Values are normalized mean ± s.e.m. (n = 3; *p-value < 0.05). d Effect of USP15 knockdown on cell viability in ovarian cancer cells carrying different p53 mutation status. Values are normalized mean ± s.e.m. (n = 3; *p-value = 0.0164). e USP15 knockdown significantly reduced the anchorage-independent growth of TYK-Nu cells (p53-R175H). Values are normalized mean ± s.d. (n = 4; **p-value = 0.006). f Data retrieved from Oncomine showing elevated USP15 mRNA levels in multiple cancers from previously published datasets^{29, 39,40,41,42}. g Schematic showing that different pathways regulate the stability of p53-R175H and p53-WT in ovarian cancer cells. MCB-613 and DUB inhibitors, such as NSC632839 and PR-619 caused selective depletion of the GOF p53 mutant p53-R175H, while causing slight increase in p53-WT levels. While inhibition of USP15 by these small molecules or siRNA resulted in increased ubiquitination and lysosome-mediated turnover of p53-R175H, it had no effect on p53-WT levels. In contrast, USP7 depletion caused MDM2-mediated stabilization of p53-WT protein