Galactosyltransferase B4GALT1 confers chemoresistance in pancreatic ductal adenocarcinomas by upregulating N-linked glycosylation of CDK11p110. (1st March 2021)

• Record Type: Journal Article
• Authors: Chen, Yitian; Su, Liangping; Huang, Cheng; Wu, Sangqing; Qiu, Xiaoyi; Zhao, Xinbao; Meng, Qiong; Meng, Ya-Ming; Kong, Xiangzhan; Wang, Minghui; Liu, Chao; Wong, Ping-Pui
• Is Part Of: Cancer letters. Volume 500(2021)
• Page Start: 228
• Page End: 243
• Publication Date: 2021-03-01
• Subjects: B4GALT1 -- CDK11p110 -- Pancreatic ductal adenocarcinomas -- N-linked glycosylation -- Chemoresistance; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2020.12.006
• Languages: English
• ISSNs: 0304-3835

Abstract

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 CDK11 p110 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-CDK11 p110 signalling axis determines cancer progression and chemoresistance, providing a new therapeutic target for an improved pancreatic cancer treatment. Highlights: High B4GALT1 expression associates with poor prognosis and response to chemotherapy in PDAC patients. Aberrant expression of B4GALT1 regulates migration, invasion, sphere formation and chemoresistance. Elevated p65 activity up-regulates B4GALT1 mediated N-linked glycosylation in CDK11 p110 to promote cancer progression. B4GALT1 depletion rescues the response of chemoresistant cells to gemcitabine in an orthotopic PDAC model.