UBE2O promotes lipid metabolic reprogramming and liver cancer progression by mediating HADHA ubiquitination

Cancer cells rely on heightened protein quality control mechanisms, including the ubiquitin-proteosome system that is predominantly driven by ubiquitination comprising E1, E2, and E3 trienzyme cascades. Although E3s have been extensively studied, the implication of E2s in tumorigenesis is poorly def...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Oncogene 2022-11, Vol.41 (48), p.5199-5213
Hauptverfasser: Ma, Meilin, Zhang, Changhui, Cao, Rong, Tang, Dongmei, Sang, Xiongbo, Zou, Sailan, Wang, Xiuxuan, Xu, Haixia, Liu, Geng, Dai, Lunzhi, Tian, Yan, Gao, Xiang, Fu, Xianghui
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung:Cancer cells rely on heightened protein quality control mechanisms, including the ubiquitin-proteosome system that is predominantly driven by ubiquitination comprising E1, E2, and E3 trienzyme cascades. Although E3s have been extensively studied, the implication of E2s in tumorigenesis is poorly defined. Here we reveal a critical E2 in the pathogenesis of hepatocellular carcinoma (HCC). Among all of E2s, UBE2O shows the strongest association with HCC survival prognosis, and its expression is increased in HCC tumors. Accordingly, UBE2O deficiency inhibits HCC growth and metastasis both in vitro and in vivo, while its overexpression has opposite effects. Depending on both E2 and E3 enzymatic activities, UBE2O can interact with and mediate the ubiquitination and degradation of HADHA, a mitochondrial β-oxidation enzyme, thereby modulating lipid metabolic reprogramming. HADHA is reduced in HCC tumors and inversely correlated with UBE2O levels. Importantly, HADHA acts as a tumor suppressor and primarily mediates UBE2O’s function on HCC. Moreover, liver-specific deletion of Ube2o in mice are resistant to DEN-induced hepatocarcinogenesis, along with HADHA upregulation and reduced hepatic lipid accumulation. These data reveal UBE2O as a novel oncogenic driver for metabolic reprogramming and HCC development, highlighting the potential of targeting UBE2O/HADHA axis for HCC therapy.
ISSN:0950-9232
1476-5594
DOI:10.1038/s41388-022-02509-1