The deubiquitinase USP10 protects pancreatic cancer cells from endoplasmic reticulum stress

Abstract

The ubiquitin-specific peptidase 10 (USP10) plays a context-specific, pro or anti-tumorigenic role in different malignancies. However, the role of USP10 in pancreatic cancer remains unclear. Our protein and RNA level analysis from archived specimens and public databases show that USP10 is overexpressed in pancreatic ductal adenocarcinoma (PDAC) and expression correlates with poor overall patient survival. Phenotypically, silencing USP10 decreased viability, clonal growth and invasive properties of pancreatic cancer cells. Mechanistically, silencing USP10 upregulated BiP and induced endoplasmic reticulum (ER) stress that led to an unfolded protein response (UPR) and upregulation of PERK, IRE1α. Decreased cell viability of USP10 silenced cells could be rescued by a chemical chaperone that promotes protein folding. Our studies suggest that USP10 by protecting pancreatic cancer cells from ER stress may support tumor progression.

The role of deubiquitinases in cardiac disease

“…Several studies have shown that the accumulation of ubiquitinated proteins induced by deubiquitinase can lead to endoplasmic reticulum (ER) stress and activation of autophagy (Refs 120 , 121 ). Both broad-spectrum inhibitors of deubiquitinases and specific inhibitors of individual deubiquitinases can lead to an increase in the ubiquitination of total proteins, thereby activating ER stress, unfolded protein response and AMPK pathway-mediated autophagy (Refs 122 , 123 ).…”

Stress granules in cancer: Adaptive dynamics and therapeutic implications

“… 115 In pancreatic cancer, USP10 acts to protect cancer cells from apoptosis induced by ER stress. 116 …”