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Immature truncated O-glycophenotype of cancer directly induces oncogenic features.

ABSTRACT: Aberrant expression of immature truncated O-glycans is a characteristic feature observed on virtually all epithelial cancer cells, and a very high frequency is observed in early epithelial premalignant lesions that precede the development of adenocarcinomas. Expression of the truncated O-glycan structures Tn and sialyl-Tn is strongly associated with poor prognosis and overall low survival. The genetic and biosynthetic mechanisms leading to accumulation of truncated O-glycans are not fully understood and include mutation or dysregulation of glycosyltransferases involved in elongation of O-glycans, as well as relocation of glycosyltransferases controlling initiation of O-glycosylation from Golgi to endoplasmic reticulum. Truncated O-glycans have been proposed to play functional roles for cancer-cell invasiveness, but our understanding of the biological functions of aberrant glycosylation in cancer is still highly limited. Here, we used exome sequencing of most glycosyltransferases in a large series of primary and metastatic pancreatic cancers to rule out somatic mutations as a cause of expression of truncated O-glycans. Instead, we found hypermethylation of core 1 ?3-Gal-T-specific molecular chaperone, a key chaperone for O-glycan elongation, as the most prevalent cause. We next used gene editing to produce isogenic cell systems with and without homogenous truncated O-glycans that enabled, to our knowledge, the first polyomic and side-by-side evaluation of the cancer O-glycophenotype in an organotypic tissue model and in xenografts. The results strongly suggest that truncation of O-glycans directly induces oncogenic features of cell growth and invasion. The study provides support for targeting cancer-specific truncated O-glycans with immunotherapeutic measures.

SUBMITTER: Radhakrishnan P

PROVIDER: S-EPMC4191756 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Immature truncated O-glycophenotype of cancer directly induces oncogenic features.

Radhakrishnan Prakash P Dabelsteen Sally S Madsen Frey Brus FB Francavilla Chiara C Kopp Katharina L KL Steentoft Catharina C Vakhrushev Sergey Y SY Olsen Jesper V JV Hansen Lars L Bennett Eric P EP Woetmann Anders A Yin Guangliang G Chen Longyun L Song Haiyan H Bak Mads M Hlady Ryan A RA Peters Staci L SL Opavsky Rene R Thode Christenze C Qvortrup Klaus K Schjoldager Katrine T-B G KT Clausen Henrik H Hollingsworth Michael A MA Wandall Hans H HH

Proceedings of the National Academy of Sciences of the United States of America 20140812 39

Aberrant expression of immature truncated O-glycans is a characteristic feature observed on virtually all epithelial cancer cells, and a very high frequency is observed in early epithelial premalignant lesions that precede the development of adenocarcinomas. Expression of the truncated O-glycan structures Tn and sialyl-Tn is strongly associated with poor prognosis and overall low survival. The genetic and biosynthetic mechanisms leading to accumulation of truncated O-glycans are not fully unders ...[more]

PMID: 25118277

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Immature truncated O-glycophenotype of cancer directly induces oncogenic features.

Publications

Immature truncated O-glycophenotype of cancer directly induces oncogenic features.

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