journal article·2024-12Open access

MGAT4A/Galectin9‐Driven N ‐Glycosylation Aberration as a Promoting Mechanism for Poor Prognosis of Endometrial Cancer with TP53 Mutation

Zhen Zhu, Jingya Sun, Weiqing Xu, Qinghe Zeng, Hanyi Feng, Lijuan Zang, Yinyan He, Xiao He, Na Sheng, Xuelian Ren, Guobin Liu, He Huang, Ruimin Huang, Jun Yan

Advanced Science· Volume 11· Issue 48

Abstract

Abstract Emerging evidence recognizes aberrant glycosylation as the malignant characteristics of cancer cells, but little is known about glycogenes’ roles in endometrial carcinoma (EC), especially the most aggressive subtype carrying TP53 mutations. Using unsupervised hierarchical clustering, an 11‐glycogene cluster is identified to distinguish an EC subtype associated with frequent TP53 mutation and worse prognosis. Among them, MGAT4A (alpha‐1,3‐mannosyl‐glycoprotein 4‐β‐ N ‐acetylglucosaminyltransferase A) emerges as the most consistently overexpressed glycogene, contributing to EC aggressiveness. In the presence of galectin‐9, MGAT4A increases EC cell proliferation and invasion via promoting glucose metabolism. N‐ glycoproteomics further revealed GLUT1, a glucose transporter, as a glycoprotein modified by MGAT4A. Binding of galectin‐9 to the MGAT4A‐branched N‐ glycan on GLUT1 enhances its cell membrane distribution, leading to glucose uptake increase. In addition, oncogenic mutations of TP53 gene in EC cells upregulate MGAT4A expression by disrupting the regulatory oversight exerted by wild‐type p53 on tumor‐suppressive miRNAs, including miR‐34a and miR‐449a/b. The findings highlight a new molecular mechanism involving MGAT4A‐regulated N‐ glycosylation on the key regulator of glucose metabolism in p53 mutants‐driven EC aggressiveness, which may provide a strategic avenue to combat advanced EC.
Source: crossref · Quality: baseline

Research context

OpenAlex topics: Galectins and Cancer Biology · Signaling Pathways in Disease · Glycosylation and Glycoproteins Research

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Center for Medical Research and Innovation Shanghai Pudong Hospital Fudan University Pudong Medical Center; Laboratory Animal Center Fudan University Shanghai 200032 China

Model Animal Research Center of Nanjing University Nanjing 210061 China

Center for Drug Safety Evaluation and Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 China

Department of Pathology Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200080 China

School of Chinese Materia Medica Nanjing University of Chinese Medicine Nanjing 210023 China

Department of Obstetrics and Gynecology Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200080 China

Department of Obstetrics and Gynecology Shanghai Tenth People's Hospital Tongji University School of Medicine Shanghai 200072 China

State Key Laboratory of Chemical Biology Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 China

University of Chinese Academy of Sciences Beijing 100049 China

School of Pharmaceutical Science and Technology Hangzhou Institute for Advanced Study University of Chinese Academy of Sciences Hangzhou 310024 China

Funding

National Natural Science Foundation of China · Science and Technology Commission of Shanghai Municipality

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