USP35 mitigates endoplasmic reticulum stress‐induced apoptosis by stabilizing RRBP1 in non‐small cell lung cancer

Abstract

Deubiquitinating enzymes (DUBs) serve to maintain cellular homeostasis via protein ubiquitination and exert diverse regulatory functions in cancers and other diseases. Much progress has been made in characterizing biological roles of DUBs over the decades, yet the specific functions of many subclass members remain largely unexplored. It was not until recent years that the role of ubiquitin-specific-processing protease 35 (USP35) in cancers began to be understood. Here, we focus on delineating the roles and underlying mechanisms of USP35 in non-small cell lung cancer (NSCLC). The isobaric tags for relative and absolute quantitation (iTRAQ) comparative proteomic approach were employed to identify differentially expressed proteins (DEPs) in H1299 cells induced by USP35 overexpression or silencing. Among the potential interactome of USP35, ribosome-binding protein 1 (RRBP1), a membrane-bound protein in endoplasmic reticulum (ER), captured our attentions. RRBP1 expression was found to positively correlate with USP35 levels in both genetically modified cells and human NSCLC tissues. Concordantly, both RRBP1 expression and USP35 expression were found to positively correlate with poor prognoses in lung adenocarcinoma patients. At the molecular level, USP35 was verified to directly interact with RRBP1 to prevent it from proteasomal-dependent degradation. Functionally, USP35 alleviated ER stress-induced cell apoptosis by stabilizing RRBP1 in NSCLC cells. Collectively, these findings indicate that USP35 plays a critical role in resisting ER stress-induced cell death through deubiquitinating RRBP1, hence providing a rationale to target the USP35-RRBP1 axis as an alternative therapeutic option for NSCLC.

Deubiquitinases in Cancers: Aspects of Proliferation, Metastasis, and Apoptosis

“…Several DUBs, such as USP1 and USP35, are known to play roles in DNA repair [ 189 ]. USP35 stabilizes ribosome binding protein 1 (RRBP1) and reduces endoplasmic reticulum stress-induced apoptosis in NSCL [ 190 ]. It targets ferroportin and is related to ferroptosis [ 191 ].…”

Mitochondria, mitophagy, and the role of deubiquitinases as novel therapeutic targets in liver pathology

“…It is not well‐understood how the USP35 complex (short‐USP35 and long‐USP35) contributes to mitochondrial quality control, but some evidence suggests that USP35 acts as a housekeeping factor in healthy mitochondria since it maintains the level of mitochondrial morphology proteins such as MFN2. As a result of mitochondrial depolarization, the USP35 complex detaches from altered mitochondria, allowing PARK2 to perform its function 34 …”

“…As a result of mitochondrial depolarization, the USP35 complex detaches from altered mitochondria, allowing PARK2 to perform its function. 34 Clinical studies revealed that USP35 expression is upregulated in HCC when compared to corresponding normal tissues. 35 The upregulation in USP35 seems to be not limited to HCC as other studies showed also upregulation of USP35 expression in lung, ovarian, colon adenocarcinoma, and head and neck cancer.…”

Endoplasmic Reticulum Stress-Related Four-Biomarker Risk Classifier for Survival Evaluation in Esophageal Cancer

“…Furthermore, ER stress-related genes (ERGs) are proved to display a central part role in the aggravation of cancer. In lung cancer, USP35 could regulate apoptosis triggered by ER stress through stabilization of RRBP1 [ 13 ]. DDX5, also named P68, is required for EC suppression in an ER stress relevant way [ 14 ].…”