The Tumor-Associated Glycosyltransferase ST6Gal-I Regulates Stem Cell Transcription Factors and Confers a Cancer Stem Cell Phenotype.

Academic Article

Abstract

  • The glycosyltransferase ST6Gal-I, which adds α2-6-linked sialic acids to substrate glycoproteins, has been implicated in carcinogenesis; however, the nature of its pathogenic role remains poorly understood. Here we show that ST6Gal-I is upregulated in ovarian and pancreatic carcinomas, enriched in metastatic tumors, and associated with reduced patient survival. Notably, ST6Gal-I upregulation in cancer cells conferred hallmark cancer stem-like cell (CSC) characteristics. Modulating ST6Gal-I expression in pancreatic and ovarian cancer cells directly altered CSC spheroid growth, and clonal variants with high ST6Gal-I activity preferentially survived in CSC culture. Primary ovarian cancer cells from patient ascites or solid tumors sorted for α2-6 sialylation grew as spheroids, while cells lacking α2-6 sialylation remained as single cells and lost viability. ST6Gal-I also promoted resistance to gemcitabine and enabled the formation of stably resistant colonies. Gemcitabine treatment of patient-derived xenograft tumors enriched for ST6Gal-I-expressing cells relative to pair-matched untreated tumors. ST6Gal-I also augmented tumor-initiating potential. In limiting dilution assays, subcutaneous tumor formation was inhibited by ST6Gal-I knockdown, whereas in a chemically induced tumor initiation model, mice with conditional ST6Gal-I overexpression exhibited enhanced tumorigenesis. Finally, we found that ST6Gal-I induced expression of the key tumor-promoting transcription factors, Sox9 and Slug. Collectively, this work highlighted a previously unrecognized role for a specific glycosyltransferase in driving a CSC state. Cancer Res; 76(13); 3978-88. ©2016 AACR.
  • Published In

  • Cancer Research  Journal
  • Keywords

  • Animals, Antigens, CD, Antineoplastic Combined Chemotherapy Protocols, Apoptosis, Biomarkers, Tumor, Case-Control Studies, Cell Proliferation, Cohort Studies, Female, Glycosylation, Humans, Lymphatic Metastasis, Mice, Mice, Inbred C57BL, Mice, Inbred NOD, Mice, SCID, Mice, Transgenic, Neoplasm Staging, Neoplastic Stem Cells, Ovarian Neoplasms, Pancreatic Neoplasms, Phenotype, Prognosis, SOX9 Transcription Factor, Sialyltransferases, Snail Family Transcription Factors, Survival Rate, Transcription Factors, Tumor Cells, Cultured, Xenograft Model Antitumor Assays
  • Digital Object Identifier (doi)

    Pubmed Id

  • 22882257
  • Author List

  • Schultz MJ; Holdbrooks AT; Chakraborty A; Grizzle WE; Landen CN; Buchsbaum DJ; Conner MG; Arend RC; Yoon KJ; Klug CA
  • Start Page

  • 3978
  • End Page

  • 3988
  • Volume

  • 76
  • Issue

  • 13