Open AccessDeficiency of pseudogene UPAT leads to hepatocellular carcinoma progression and forms a positive feedback loop with ZEB1
Author(s) -
Xiang Leyang,
Huang Xiaoting,
Wang Siqi,
Ou Huohui,
Chen Zhanjun,
Hu Zhigang,
Huang Yu,
Li Xianghong,
Yuan Yawei,
Yang Dinghua
Publication year - 2020
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.14620
Subject(s) - hepatocellular carcinoma , cancer research , downregulation and upregulation , ubiquitin , metastasis , proteasome , epithelial–mesenchymal transition , in vivo , liver cancer , cancer , biology , carcinoma , medicine , gene , microbiology and biotechnology , biochemistry
Abstract 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.