USP35 mitigates endoplasmic reticulum stress‐induced apoptosis by stabilizing RRBP1 in non‐small cell lung cancer
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...
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Veröffentlicht in: | Molecular oncology 2022-04, Vol.16 (7), p.1572-1590 |
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Zusammenfassung: | 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.
Ribosome‐binding protein 1 (RRBP1) was found to positively correlate with ubiquitin‐specific protease 35 (USP35) levels by proteomic analysis, which was validated in genetically modified cells and human non‐small cell lung cancer (NSCLC) tissues. USP35 was verified to interact with RRBP1 and prevent it from proteasomal‐dependent degradation. USP35 alleviated endoplasmic reticulum stress‐induced cell apoptosis by stabilizing RRBP1 in NSCLC cells. |
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ISSN: | 1574-7891 1878-0261 |
DOI: | 10.1002/1878-0261.13112 |