Tumor suppressor DCAF15 inhibits epithelial-mesenchymal transition by targeting ZEB1 for proteasomal degradation in hepatocellular carcinoma
Epithelial-mesenchymal transition (EMT) is an evolutionarily conserved developmental program that has been implicated in tumorigenesis and confers metastatic properties upon cancer cells. ZEB1 is a master transcription factor that activates the EMT process in various cancers. ZEB1 is reportedly degraded through the ubiquitin proteasome pathway, but the underlying molecular mechanism of this process remains largely unknown in hepatocellular carcinoma (HCC). Here, we identified ZEB1 as a substrate of the CRL4-DCAF15 (DDB1 and CUL4 associated factor 15) E3 ubiquitin ligase complex. DCAF15 acts as an adaptor that specifically recognizes the N-terminal zinc finger domain of ZEB1, then triggers its degradation via the ubiquitin-proteasome pathway. DCAF15 knockdown led to upregulation of ZEB1 and activation of EMT, whereas overexpression of DCAF15 suppressed ZEB1 and inhibited EMT. DCAF15 knockdown also promoted HCC cell proliferation and invasion in a ZEB1-dependent manner. In HCC patients, low DCAF15 expression was predictive of an unfavorable prognosis. These findings reveal the distinct molecular mechanism by which DCAF15 suppresses HCC malignancy and provides insight into the relationship between the CUL4-DCAF15 E3 ubiquitin ligase complex and ZEB1 in HCC.
Medienart: |
E-Artikel |
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Erscheinungsjahr: |
2021 |
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Erschienen: |
2021 |
Enthalten in: |
Zur Gesamtaufnahme - volume:13 |
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Enthalten in: |
Aging - 13(2021), 7 vom: 04. Apr., Seite 10603-10618 |
Sprache: |
Englisch |
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Beteiligte Personen: |
Dong, Xiao [VerfasserIn] |
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Links: |
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Anmerkungen: |
Date Completed 19.07.2021 Date Revised 19.07.2021 published: Print-Electronic Citation Status MEDLINE |
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doi: |
10.18632/aging.202823 |
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funding: |
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Förderinstitution / Projekttitel: |
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PPN (Katalog-ID): |
NLM323882919 |
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245 | 1 | 0 | |a Tumor suppressor DCAF15 inhibits epithelial-mesenchymal transition by targeting ZEB1 for proteasomal degradation in hepatocellular carcinoma |
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520 | |a Epithelial-mesenchymal transition (EMT) is an evolutionarily conserved developmental program that has been implicated in tumorigenesis and confers metastatic properties upon cancer cells. ZEB1 is a master transcription factor that activates the EMT process in various cancers. ZEB1 is reportedly degraded through the ubiquitin proteasome pathway, but the underlying molecular mechanism of this process remains largely unknown in hepatocellular carcinoma (HCC). Here, we identified ZEB1 as a substrate of the CRL4-DCAF15 (DDB1 and CUL4 associated factor 15) E3 ubiquitin ligase complex. DCAF15 acts as an adaptor that specifically recognizes the N-terminal zinc finger domain of ZEB1, then triggers its degradation via the ubiquitin-proteasome pathway. DCAF15 knockdown led to upregulation of ZEB1 and activation of EMT, whereas overexpression of DCAF15 suppressed ZEB1 and inhibited EMT. DCAF15 knockdown also promoted HCC cell proliferation and invasion in a ZEB1-dependent manner. In HCC patients, low DCAF15 expression was predictive of an unfavorable prognosis. These findings reveal the distinct molecular mechanism by which DCAF15 suppresses HCC malignancy and provides insight into the relationship between the CUL4-DCAF15 E3 ubiquitin ligase complex and ZEB1 in HCC | ||
650 | 4 | |a Journal Article | |
650 | 4 | |a Research Support, Non-U.S. Gov't | |
650 | 4 | |a DCAF15 | |
650 | 4 | |a ZEB1 | |
650 | 4 | |a epithelial-mesenchymal transition | |
650 | 4 | |a hepatocellular carcinoma | |
650 | 4 | |a ubiquitination | |
650 | 7 | |a DCAF15 protein, human |2 NLM | |
650 | 7 | |a Intracellular Signaling Peptides and Proteins |2 NLM | |
650 | 7 | |a ZEB1 protein, human |2 NLM | |
650 | 7 | |a Zinc Finger E-box-Binding Homeobox 1 |2 NLM | |
650 | 7 | |a Proteasome Endopeptidase Complex |2 NLM | |
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700 | 1 | |a Han, Yang |e verfasserin |4 aut | |
700 | 1 | |a Zhang, Encheng |e verfasserin |4 aut | |
700 | 1 | |a Wang, Yuqi |e verfasserin |4 aut | |
700 | 1 | |a Zhang, Pingzhao |e verfasserin |4 aut | |
700 | 1 | |a Wang, Chenji |e verfasserin |4 aut | |
700 | 1 | |a Zhong, Lin |e verfasserin |4 aut | |
700 | 1 | |a Li, Qi |e verfasserin |4 aut | |
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