Ubiquitin ligase CHIP regulates OTUD3 stability and suppresses tumour metastasis in lung cancer

Ovarian tumour domain-containing protein 3 (OTUD3), a key OTU (ovarian tumour protease) family deubiquitylase, plays context-dependent roles in cancers. It suppresses tumorigenesis in breast, colon, liver and cervical cancer through stabilizing PTEN (phosphatase and tension homologue deleted on chro...

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Bibliographic Details
Published in:Cell death and differentiation 2020-11, Vol.27 (11), p.3177-3195
Main Authors: Zhang, Pengfei, Li, Chaonan, Li, Hongchang, Yuan, Lin, Dai, Hongmiao, Peng, Zhiqiang, Deng, Zhikang, Chang, Zhijie, Cui, Chun-Ping, Zhang, Lingqiang
Format: Article
Language:English
Subjects:
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Apoptosis
Biochemistry
Biomedical and Life Sciences
Breast
Cell Biology
Cell Cycle Analysis
Cervical cancer
Cervix
Chromosome 10
Colon
Colon cancer
Hsc70 protein
Life Sciences
Liver cancer
Lung cancer
Metastases
Metastasis
Ovarian cancer
Ovaries
Post-translation
Proteins
PTEN protein
Stem Cells
Tumorigenesis
Tumors
Ubiquitin
Ubiquitin-protein ligase
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Summary:Ovarian tumour domain-containing protein 3 (OTUD3), a key OTU (ovarian tumour protease) family deubiquitylase, plays context-dependent roles in cancers. It suppresses tumorigenesis in breast, colon, liver and cervical cancer through stabilizing PTEN (phosphatase and tension homologue deleted on chromosome 10) while promotes lung tumorigenesis through stabilizing GRP78 (The glucose-regulated protein 78 kDa). The regulation especially post-translational modification of OTUD3 remains unclear. Here, we report that the carboxyl terminus of Hsc70-interacting protein (CHIP) is a ubiquitin ligase for OTUD3. CHIP interacts with, polyubiquitylates OTUD3 and promotes OTUD3 degradation. Knockdown of CHIP stabilizes OTUD3 which leads to elevated GRP78 levels in lung cancer cells. CHIP-knockdown lung cancer cells exhibit increased invasion in OTUD3 and GRP78 dependent manner. Further study demonstrates that CHIP-knockdown lung cancer cells are more prone to metastasize to mice lung when injected intravenously or subcutaneously. Moreover, the expression of CHIP is low in human lung cancer tissues and inversely correlates with OTUD3 expression and GRP78 expression. Furthermore, we identified CHIP mutations in human lung cancers, which reduce CHIP catalytic activity. These findings demonstrate that CHIP is a negative regulator of OTUD3 and CHIP suppresses lung cancer metastasis through inhibiting OTUD3-GRP78 signaling axis.
ISSN:1350-9047
1476-5403
DOI:10.1038/s41418-020-0571-7