Deficiency of pseudogene UPAT leads to hepatocellular carcinoma progression and forms a positive feedback loop with ZEB1.
Hepatocellular carcinoma (HCC) is a common disease worldwide. Accumulating reports have evidenced the internal connection between epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs), as well as their significance in metastasis and post-operative recurrence. In this study, we investigated an interesting ubiquitin-proteasome pathway associated pseudogene of AOC4, also known as UPAT, and showed that it was downregulated in 39.78% (37/93) of patients with hepatitis B virus (HBV)-related HCC. Downregulation of UPAT was associated with multiple worse clinicopathological parameters, as well as decreased recurrence-free survival (RFS). In vitro and in vivo assays found that overexpression of UPAT significantly suppressed cellular migration, invasion, EMT processes, and CSC properties. Mechanistic studies showed that UPAT promoted ZEB1 degradation via a ubiquitin-proteasome pathway and, in contrast, ZEB1 transcriptionally suppressed UPAT by binding to multiple E-box (CACCTG) elements in the promoter region. Moreover, UPAT was negatively correlated with ZEB1 protein in HCC tissues, their combined expression discriminated RFS outcomes for patients with HBV-related HCC. These data on the UPAT-ZEB1 circuit-mediated pathway will further knowledge on EMT and CSCs, and may help to develop novel therapeutic approaches for the prevention of HCC metastasis.
['Xiang|Leyang|L|', 'Huang|Xiaoting|X|', 'Wang|Siqi|S|', 'Ou|Huohui|H|', 'Chen|Zhanjun|Z|', 'Hu|Zhigang|Z|', 'Huang|Yu|Y|', 'Li|Xianghong|X|', 'Yuan|Yawei|Y|', 'Yang|Dinghua|D|https://orcid.org/0000-0002-1442-5240']
D000368:Aged D000818:Animals D015415:Biomarkers D014408:Biomarkers, Tumor D006528:Carcinoma, Hepatocellular D045744:Cell Line, Tumor D002465:Cell Movement D018450:Disease Progression D005260:Female D017353:Gene Deletion D015972:Gene Expression Regulation, Neoplastic D006801:Humans D007150:Immunohistochemistry D008113:Liver Neoplasms D008297:Male D051379:Mice D008875:Middle Aged D011379:Prognosis D011544:Pseudogenes D062085:RNA, Long Noncoding D000071799:Zinc Finger E-box-Binding Homeobox 1
UPAT hepatocellular carcinoma ZEB1 epithelial-mesenchymal transition stemness