title: The Tumor-Associated Glycosyltransferase ST6Gal-I Regulates Stem Cell Transcription Factors and Confers a Cancer Stem Cell Phenotype.
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.
authors.affiliation: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Schultz
authors.affiliation: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Holdbrooks
authors.affiliation: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Asmi
authors.initials: A
authors.lastname: Chakraborty
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: William E
authors.initials: WE
authors.lastname: Grizzle
authors.affiliation: Department of Obstetrics and Gynecology, University of Virginia, Charlottesville, Virginia.
authors.forename: Charles N
authors.initials: CN
authors.lastname: Landen
authors.affiliation: Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Buchsbaum
authors.affiliation: Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Conner
authors.affiliation: Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Arend
authors.affiliation: Department of Pharmacology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Karina J
authors.initials: KJ
authors.lastname: Yoon
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Klug
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Bullard
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Kesterson
authors.affiliation: Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Patsy G
authors.initials: PG
authors.lastname: Oliver
authors.affiliation: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Amber K
authors.initials: AK
authors.lastname: O'Connor
authors.affiliation: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Bradley K
authors.initials: BK
authors.lastname: Yoder
authors.affiliation: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama. bellis@uab.edu.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Bellis
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis; D014408:Biomarkers, Tumor; D016022:Case-Control Studies; D049109:Cell Proliferation; D015331:Cohort Studies; D005260:Female; D006031:Glycosylation; D006801:Humans; D008207:Lymphatic Metastasis; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D009367:Neoplasm Staging; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D011379:Prognosis; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism; D012799:Sialyltransferases / Q000235:genetics / Q000378:metabolism*; D000071250:Snail Family Transcription Factors / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase
chemical_list: D015703:Antigens, CD; D014408:Biomarkers, Tumor; D055758:SOX9 Transcription Factor; D012799:Sialyltransferases; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C000604407:SNAI1 protein, human; C527932:SOX9 protein, human; C093493:ST6GAL1 protein, human; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase