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

Cancer Res. 2016 Jul 1;76(13):3978-88. doi: 10.1158/0008-5472.CAN-15-2834. Epub 2016 May 23.


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.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / metabolism*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • 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 / metabolism
  • Neoplastic Stem Cells / pathology*
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology*
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology*
  • Phenotype
  • Prognosis
  • SOX9 Transcription Factor / genetics
  • SOX9 Transcription Factor / metabolism
  • Sialyltransferases / genetics
  • Sialyltransferases / metabolism*
  • Snail Family Transcription Factors / genetics
  • Snail Family Transcription Factors / metabolism
  • Survival Rate
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays


  • Antigens, CD
  • Biomarkers, Tumor
  • SNAI1 protein, human
  • SOX9 Transcription Factor
  • SOX9 protein, human
  • Snail Family Transcription Factors
  • Transcription Factors
  • Sialyltransferases
  • ST6GAL1 protein, human