Galactosyltransferase B4GALT1 confers chemoresistance in pancreatic ductal adenocarcinomas by upregulating N-linked glycosylation of CDK11p110.

Abstract

Aberrant glycosylation in pancreatic cancer has been linked to cancer development, progression and chemoresistance. However, the role of glycogene, such as galactosyltransferase, in pancreatic cancer remains unknown. Herein, we establish beta-1.4-galactosyltransferase 1 (B4GALT1) as a clinical marker and regulator of chemoresistance. Clinically, high B4GALT1 expression correlates with poor survival, enhanced tumor size, increased lymph node metastasis, elevated cancer progression and enhanced incidence of relapse in PDAC patients. Expression of B4GALT1 is up-regulated in gemcitabine resistant patient derived organoids as well as chemoresistant cancer cell lines, while genetic perturbation of its expression in PDAC cell lines regulates cancer progression and chemoresistance. Mechanistically, we show that elevated p65 activity transcriptionally up-regulates B4GALT1 expression, which then interacts with and stabilizes cyclin dependent kinase 11 isomer CDK11p110 protein via N-linked glycosylation, in order to promote cancer progression and chemoresistance. Finally, depletion of B4GALT1 rescues the response of chemoresistant cells to gemcitabine in an orthotopic PDAC model. Overall, our data uncovers a mechanism by which p65-B4GALT1-CDK11p110 signalling axis determines cancer progression and chemoresistance, providing a new therapeutic target for an improved pancreatic cancer treatment.

• Authors: Yitian Chen, Liangping Su, Cheng Huang, Sangqing Wu, Xiaoyi Qiu, Xinbao Zhao, Qiong Meng, Ya-Ming Meng, Xiangzhan Kong, Minghui Wang, Chao Liu, Ping-Pui Wong
• Journal: Cancer letters (Cancer Lett) Vol. 500 Pg. 228-243 (03 01 2021) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 33309857 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier B.V. All rights reserved.

Chemical References

• Transcription Factor RelA
• Deoxycytidine
• Galactosyltransferases
• beta-1,4-galactosyltransferase I
• CDK19 protein, human
• Cyclin-Dependent Kinases
• Gemcitabine

Topics

• Adenocarcinoma (drug therapy, genetics, pathology)
• Carcinoma, Pancreatic Ductal (drug therapy, genetics, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cyclin-Dependent Kinases (genetics)
• Deoxycytidine (adverse effects, analogs & derivatives, pharmacology)
• Drug Resistance, Neoplasm (genetics)
• Galactosyltransferases (genetics)
• Gene Expression Regulation, Neoplastic (drug effects)
• Glycosylation (drug effects)
• Humans
• Neoplasm Recurrence, Local (drug therapy, genetics, pathology)
• Organoids (drug effects)
• Transcription Factor RelA (genetics)
• Gemcitabine