MGAT4A/Galectin9‐Driven N‐Glycosylation Aberration as a Promoting Mechanism for Poor Prognosis of Endometrial Cancer with TP53 Mutation
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‐...
Saved in:
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2024-12-01
|
| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202409764 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850041082374520832 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Zhen Zhu |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-e7345274041041919a74dae11f25bace |
| institution | DOAJ |
| issn | 2198-3844 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-e7345274041041919a74dae11f25bace2025-08-20T02:55:53ZengWileyAdvanced Science2198-38442024-12-011148n/an/a10.1002/advs.202409764MGAT4A/Galectin9‐Driven N‐Glycosylation Aberration as a Promoting Mechanism for Poor Prognosis of Endometrial Cancer with TP53 MutationZhen Zhu0Jingya Sun1Weiqing Xu2Qinghe Zeng3Hanyi Feng4Lijuan Zang5Yinyan He6Xiao He7Na Sheng8Xuelian Ren9Guobin Liu10He Huang11Ruimin Huang12Jun Yan13Center for Medical Research and Innovation Shanghai Pudong Hospital Fudan University Pudong Medical Center; Laboratory Animal Center Fudan University Shanghai 200032 ChinaCenter for Drug Safety Evaluation and Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 ChinaDepartment of Pathology Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200080 ChinaCenter for Drug Safety Evaluation and Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 ChinaCenter for Drug Safety Evaluation and Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 ChinaDepartment of Pathology Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200080 ChinaDepartment of Obstetrics and Gynecology Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200080 ChinaCenter for Drug Safety Evaluation and Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 ChinaModel Animal Research Center of Nanjing University Nanjing 210061 ChinaState Key Laboratory of Chemical Biology Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 ChinaState Key Laboratory of Chemical Biology Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 ChinaState Key Laboratory of Chemical Biology Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 ChinaCenter for Drug Safety Evaluation and Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 ChinaCenter for Medical Research and Innovation Shanghai Pudong Hospital Fudan University Pudong Medical Center; Laboratory Animal Center Fudan University Shanghai 200032 ChinaAbstract 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.https://doi.org/10.1002/advs.202409764endometrial cancerglucose metabolismMGAT4AN‐glycosylationTP53 mutation |
| spellingShingle | 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 MGAT4A/Galectin9‐Driven N‐Glycosylation Aberration as a Promoting Mechanism for Poor Prognosis of Endometrial Cancer with TP53 Mutation Advanced Science endometrial cancer glucose metabolism MGAT4A N‐glycosylation TP53 mutation |
| title | MGAT4A/Galectin9‐Driven N‐Glycosylation Aberration as a Promoting Mechanism for Poor Prognosis of Endometrial Cancer with TP53 Mutation |
| title_full | MGAT4A/Galectin9‐Driven N‐Glycosylation Aberration as a Promoting Mechanism for Poor Prognosis of Endometrial Cancer with TP53 Mutation |
| title_fullStr | MGAT4A/Galectin9‐Driven N‐Glycosylation Aberration as a Promoting Mechanism for Poor Prognosis of Endometrial Cancer with TP53 Mutation |
| title_full_unstemmed | MGAT4A/Galectin9‐Driven N‐Glycosylation Aberration as a Promoting Mechanism for Poor Prognosis of Endometrial Cancer with TP53 Mutation |
| title_short | MGAT4A/Galectin9‐Driven N‐Glycosylation Aberration as a Promoting Mechanism for Poor Prognosis of Endometrial Cancer with TP53 Mutation |
| title_sort | mgat4a galectin9 driven n glycosylation aberration as a promoting mechanism for poor prognosis of endometrial cancer with tp53 mutation |
| topic | endometrial cancer glucose metabolism MGAT4A N‐glycosylation TP53 mutation |
| url | https://doi.org/10.1002/advs.202409764 |
| work_keys_str_mv | AT zhenzhu mgat4agalectin9drivennglycosylationaberrationasapromotingmechanismforpoorprognosisofendometrialcancerwithtp53mutation AT jingyasun mgat4agalectin9drivennglycosylationaberrationasapromotingmechanismforpoorprognosisofendometrialcancerwithtp53mutation AT weiqingxu mgat4agalectin9drivennglycosylationaberrationasapromotingmechanismforpoorprognosisofendometrialcancerwithtp53mutation AT qinghezeng mgat4agalectin9drivennglycosylationaberrationasapromotingmechanismforpoorprognosisofendometrialcancerwithtp53mutation AT hanyifeng mgat4agalectin9drivennglycosylationaberrationasapromotingmechanismforpoorprognosisofendometrialcancerwithtp53mutation AT lijuanzang mgat4agalectin9drivennglycosylationaberrationasapromotingmechanismforpoorprognosisofendometrialcancerwithtp53mutation AT yinyanhe mgat4agalectin9drivennglycosylationaberrationasapromotingmechanismforpoorprognosisofendometrialcancerwithtp53mutation AT xiaohe mgat4agalectin9drivennglycosylationaberrationasapromotingmechanismforpoorprognosisofendometrialcancerwithtp53mutation AT nasheng mgat4agalectin9drivennglycosylationaberrationasapromotingmechanismforpoorprognosisofendometrialcancerwithtp53mutation AT xuelianren mgat4agalectin9drivennglycosylationaberrationasapromotingmechanismforpoorprognosisofendometrialcancerwithtp53mutation AT guobinliu mgat4agalectin9drivennglycosylationaberrationasapromotingmechanismforpoorprognosisofendometrialcancerwithtp53mutation AT hehuang mgat4agalectin9drivennglycosylationaberrationasapromotingmechanismforpoorprognosisofendometrialcancerwithtp53mutation AT ruiminhuang mgat4agalectin9drivennglycosylationaberrationasapromotingmechanismforpoorprognosisofendometrialcancerwithtp53mutation AT junyan mgat4agalectin9drivennglycosylationaberrationasapromotingmechanismforpoorprognosisofendometrialcancerwithtp53mutation |