Research Paper Volume 13, Issue 7 pp 10603—10618
Tumor suppressor DCAF15 inhibits epithelial-mesenchymal transition by targeting ZEB1 for proteasomal degradation in hepatocellular carcinoma
- 1 Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
- 2 Institute of Translational Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China
- 3 Department of Urology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
- 4 State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200438, China
- 5 Department of Hepatobiliary and General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
Received: November 10, 2020 Accepted: March 4, 2021 Published: April 4, 2021https://doi.org/10.18632/aging.202823
How to Cite
Copyright: © 2021 Dong et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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.