TY - JOUR
T1 - The interplay of UBE2T and Mule in regulating Wnt/β-catenin activation to promote hepatocellular carcinoma progression
AU - Ho, Nicole Pui Yu
AU - Leung, Carmen Oi Ning
AU - Wong, Tin Lok
AU - Lau, Eunice Yuen Ting
AU - Lei, Martina Mang Leng
AU - Mok, Etienne Ho Kit
AU - Leung, Hoi Wing
AU - Tong, Man
AU - Ng, Irene Oi Lin
AU - Yun, Jing Ping
AU - Ma, Stephanie
AU - Lee, Terence Kin Wah
N1 - Funding Information:
We thank the University Research Facility in Life Sciences at the Hong Kong Polytechnic University for providing and maintaining the equipment and technical support needed for flow cytometry and imaging work as well as the Centralized Animal Facility at the Hong Kong Polytechnic University for supporting our animal studies. This study was supported by the RGC General Research Fund (15104618 to T.K. Lee) and the Theme-based Research Scheme project (T12-704/16-R to T. K. Lee, S. Ma, and I.O.L. Ng).
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/2
Y1 - 2021/2
N2 - Emerging evidence indicates the role of cancer stem cells (CSCs) in tumor relapse and therapeutic resistance in patients with hepatocellular carcinoma (HCC). To identify novel targets against liver CSCs, an integrative analysis of publicly available datasets involving HCC clinical and stemness-related data was employed to select genes that play crucial roles in HCC via regulation of liver CSCs. We revealed an enrichment of an interstrand cross-link repair pathway, in which ubiquitin-conjugating enzyme E2 T (UBE2T) was the most significantly upregulated. Consistently, our data showed that UBE2T was upregulated in enriched liver CSC populations. Clinically, UBE2T overexpression in HCC was further confirmed at mRNA and protein levels and was correlated with advanced tumor stage and poor patient survival. UBE2T was found to be critically involved in the regulation of liver CSCs, as evidenced by increases in self-renewal, drug resistance, tumorigenicity, and metastasis abilities. Mule, an E3 ubiquitin ligase, was identified to be the direct protein binding partner of UBE2T. Rather than the canonical role of acting as a mediator to transfer ubiquitin to E3 ligases, UBE2T is surprisingly able to physically bind and regulate the protein expression of Mule via ubiquitination. Mule was found to directly degrade β-catenin protein, and UBE2T was found to mediate liver CSC functions through direct regulation of Mule-mediated β-catenin degradation; this effect was abolished when the E2 activity of UBE2T was impaired. In conclusion, we revealed a novel UBE2T/Mule/β-catenin signaling cascade that is involved in the regulation of liver CSCs, which provides an attractive potential therapeutic target for HCC.
AB - Emerging evidence indicates the role of cancer stem cells (CSCs) in tumor relapse and therapeutic resistance in patients with hepatocellular carcinoma (HCC). To identify novel targets against liver CSCs, an integrative analysis of publicly available datasets involving HCC clinical and stemness-related data was employed to select genes that play crucial roles in HCC via regulation of liver CSCs. We revealed an enrichment of an interstrand cross-link repair pathway, in which ubiquitin-conjugating enzyme E2 T (UBE2T) was the most significantly upregulated. Consistently, our data showed that UBE2T was upregulated in enriched liver CSC populations. Clinically, UBE2T overexpression in HCC was further confirmed at mRNA and protein levels and was correlated with advanced tumor stage and poor patient survival. UBE2T was found to be critically involved in the regulation of liver CSCs, as evidenced by increases in self-renewal, drug resistance, tumorigenicity, and metastasis abilities. Mule, an E3 ubiquitin ligase, was identified to be the direct protein binding partner of UBE2T. Rather than the canonical role of acting as a mediator to transfer ubiquitin to E3 ligases, UBE2T is surprisingly able to physically bind and regulate the protein expression of Mule via ubiquitination. Mule was found to directly degrade β-catenin protein, and UBE2T was found to mediate liver CSC functions through direct regulation of Mule-mediated β-catenin degradation; this effect was abolished when the E2 activity of UBE2T was impaired. In conclusion, we revealed a novel UBE2T/Mule/β-catenin signaling cascade that is involved in the regulation of liver CSCs, which provides an attractive potential therapeutic target for HCC.
UR - http://www.scopus.com/inward/record.url?scp=85100497872&partnerID=8YFLogxK
U2 - 10.1038/s41419-021-03403-6
DO - 10.1038/s41419-021-03403-6
M3 - Journal article
C2 - 33542213
AN - SCOPUS:85100497872
SN - 2041-4889
VL - 12
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 2
M1 - 148
ER -