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

Erscheinungsjahr:

2021

Erschienen:

2021

Enthalten in:

Zur Gesamtaufnahme - volume:13

Enthalten in:

Aging - 13(2021), 7 vom: 04. Apr., Seite 10603-10618

Sprache:

Englisch

Beteiligte Personen:

Dong, Xiao [VerfasserIn]
Han, Yang [VerfasserIn]
Zhang, Encheng [VerfasserIn]
Wang, Yuqi [VerfasserIn]
Zhang, Pingzhao [VerfasserIn]
Wang, Chenji [VerfasserIn]
Zhong, Lin [VerfasserIn]
Li, Qi [VerfasserIn]

Links:

Volltext

Themen:

DCAF15
DCAF15 protein, human
EC 3.4.25.1
Epithelial-mesenchymal transition
Hepatocellular carcinoma
Intracellular Signaling Peptides and Proteins
Journal Article
Proteasome Endopeptidase Complex
Research Support, Non-U.S. Gov't
Ubiquitination
ZEB1
ZEB1 protein, human
Zinc Finger E-box-Binding Homeobox 1

Anmerkungen:

Date Completed 19.07.2021

Date Revised 19.07.2021

published: Print-Electronic

Citation Status MEDLINE

doi:

10.18632/aging.202823

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM323882919