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.

• Authors: Wenqing Wang, Meixia Wang, Yi Xiao, Yige Wang, Lijuan Ma, Lulu Guo, Xinyue Wu, Xiaoyan Lin, Pengju Zhang
• Journal: Molecular oncology (Mol Oncol) Vol. 16 Issue 7 Pg. 1572-1590 (04 2022) ISSN: 1878-0261 [Electronic] United States
• PMID: 34618999 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

Chemical References

• Carrier Proteins
• RRBP1 protein, human
• Endopeptidases
• USP35 protein, human

Topics

• Apoptosis
• Carcinoma, Non-Small-Cell Lung (genetics)
• Carrier Proteins (metabolism)
• Endopeptidases
• Endoplasmic Reticulum Stress
• Humans
• Lung Neoplasms (genetics)
• Proteomics