Open AccessReduction in O-glycome induces differentially glycosylated CD44 to promote stemness and metastasis in pancreatic cancer
Author(s) -
Frank Leon,
Parthasarathy Seshacharyulu,
Rama Krishimmakayala,
Seema Chugh,
Saswati Karmakar,
Palanisamy Nallasamy,
Raghupathy Vengoji,
Satyanarayana Rachagani,
Jesse L. Cox,
Kavita Mallya,
Surinder K. Batra,
Moorthy P. Ponnusamy
Publication year - 2021
Publication title -
oncogene
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.395
H-Index - 342
eISSN - 1476-5594
pISSN - 0950-9232
DOI - 10.1038/s41388-021-02047-2
Subject(s) - homeobox protein nanog , biology , cancer stem cell , cd44 , cancer research , pancreatic cancer , stem cell , population , cancer , immunology , microbiology and biotechnology , induced pluripotent stem cell , biochemistry , in vitro , embryonic stem cell , genetics , medicine , environmental health , gene
Aberrant protein glycosylation has been shown to have a significant contribution in aggressive cancer, including pancreatic cancer (PC). Emerging evidence has implicated the involvement of cancer stem cells (CSCs) in PC aggressiveness; however, the contribution of glycosylation on self-renewal properties and maintenance of CSC is understudied. Here, using several in vitro and in vivo models lacking C1GALT1 expression, we identified the role of aberrant O-glycosylation in stemness properties and aggressive PC metastasis. A loss in C1GALT1 was found to result in the truncation of O-glycosylation on several glycoproteins with an enrichment of Tn carbohydrate antigen. Mapping of Tn-bearing glycoproteins in C1GALT1 KO cells identified significant Tn enrichment on CSC glycoprotein CD44. Notably, a loss of C1GALT1 in PC cells was found to enhance CSC features (side population-SP, ALDH1+, and tumorspheres) and self-renewal markers NANOG, SOX9, and KLF4. Furthermore, a loss of CD44 in existing C1GALT1 KO cells decreased NANOG expression and CSC features. We determined that O-glycosylation of CD44 activates ERK/NF-kB signaling, which results in increased NANOG expression in PC cells that facilitated the alteration of CSC features, suggesting that NANOG is essential for PC stemness. Finally, we identified that loss of C1GALT1 expression was found to augment tumorigenic and metastatic potential, while an additional loss of CD44 in these cells reversed the effects. Overall, our results identified that truncation of O-glycans on CD44 increases NANOG activation that mediates increased CSC activation.