Sox2 promotes expression of the ST6Gal-I glycosyltransferase in ovarian cancer cells.

Publisher: BioMed Central Country of Publication: England NLM ID: 101474849 Publication Model: Electronic Cited Medium: Internet ISSN: 1757-2215 (Electronic) Linking ISSN: 17572215 NLM ISO Abbreviation: J Ovarian Res Subsets: MEDLINE

Original Publication: [London] : BioMed Central, c2008-

Antigens, CD/*genetics ; Cell Proliferation/*genetics ; Ovarian Neoplasms/*genetics ; SOXB1 Transcription Factors/*genetics ; Sialyltransferases/*genetics; Apoptosis/genetics ; Cell Line, Tumor ; Female ; Gene Expression Regulation, Neoplastic ; Glycosyltransferases/genetics ; Humans ; Neoplastic Stem Cells/metabolism ; Ovarian Neoplasms/pathology ; Protein Binding ; Signal Transduction/genetics

Background: The ST6Gal-I glycosyltransferase, which adds α2-6-linked sialic acids to N-glycosylated proteins is upregulated in a wide range of malignancies including ovarian cancer. Prior studies have shown that ST6Gal-I-mediated sialylation of select surface receptors remodels intracellular signaling to impart cancer stem cell (CSC) characteristics. However, the mechanisms that contribute to ST6Gal-I expression in stem-like cancer cells are poorly understood.
Results: Herein, we identify the master stem cell transcription factor, Sox2, as a novel regulator of ST6Gal-I expression. Interestingly, SOX2 and ST6GAL1 are located within the same tumor-associated amplicon, 3q26, and these two genes exhibit coordinate gains in copy number across multiple cancers including ~ 25% of ovarian serious adenocarcinomas. In conjunction with genetic co-amplification, our studies suggest that Sox2 directly binds the ST6GAL1 promoter to drive transcription. ST6Gal-I expression is directed by at least four distinct promoters, and we identified the P3 promoter as the predominant promoter utilized by ovarian cancer cells. Chromatin Immunoprecipitation (ChIP) assays revealed that Sox2 binds regions proximal to the P3 promoter. To confirm that Sox2 regulates ST6Gal-I expression, Sox2 was either overexpressed or knocked-down in various ovarian cancer cell lines. Sox2 overexpression induced an increase in ST6Gal-I mRNA and protein, as well as surface α2-6 sialylation, whereas Sox2 knock-down suppressed levels of ST6Gal-I mRNA, protein and surface α2-6 sialylation.
Conclusions: These data suggest a process whereby SOX2 and ST6GAL1 are coordinately amplified in cancer cells, with the Sox2 protein then binding the ST6GAL1 promoter to further augment ST6Gal-I expression. Our collective results provide new insight into mechanisms that upregulate ST6Gal-I expression in ovarian cancer cells, and also point to the possibility that some of the CSC characteristics commonly attributed to Sox2 may, in part, be mediated through the sialyltransferase activity of ST6Gal-I.

J Biol Chem. 1994 Apr 8;269(14):10637-43. (PMID: 8144653)
Asian Pac J Cancer Prev. 2014;15(3):1181-6. (PMID: 24606438)
Biochem Biophys Res Commun. 2003 Aug 8;307(4):1070-4. (PMID: 12878221)
Glycobiology. 1996 Apr;6(3):271-9. (PMID: 8724135)
Cancer Res. 2005 Jun 1;65(11):4645-52. (PMID: 15930282)
J Ovarian Res. 2013 Apr 11;6(1):25. (PMID: 23578204)
Gynecol Oncol. 2003 Jun;89(3):395-401. (PMID: 12798701)
Cell. 2013 May 23;153(5):1149-63. (PMID: 23664763)
Biochim Biophys Acta. 2001 May 31;1536(2-3):148-60. (PMID: 11406350)
Cell Cycle. 2013 Nov 15;12(22):3471-7. (PMID: 24107627)
Sci Rep. 2015 Aug 25;5:13317. (PMID: 26304831)
Glycobiology. 2004 Jan;14(1):39-49. (PMID: 14514712)
Clin Cancer Res. 2013 Oct 15;19(20):5580-90. (PMID: 23908357)
Genes Chromosomes Cancer. 2008 Oct;47(10):890-905. (PMID: 18618715)
Pigment Cell Res. 2007 Jun;20(3):216-21. (PMID: 17516929)
Cell. 2016 Mar 24;165(1):61-74. (PMID: 27015307)
PLoS Genet. 2013;9(2):e1003288. (PMID: 23437007)
Acta Biochim Biophys Sin (Shanghai). 2010 Sep;42(9):593-602. (PMID: 20705681)
Oncogene. 2014 Sep 18;33(38):4697-708. (PMID: 24681955)
J Biol Chem. 2018 Apr 13;293(15):5659-5667. (PMID: 29475939)
Glycobiology. 2001 May;11(5):407-12. (PMID: 11425801)
Cancer Sci. 2017 Apr;108(4):719-731. (PMID: 28165651)
Int J Cancer. 2019 Nov 15;145(10):2670-2681. (PMID: 30892690)
Oncotarget. 2017 Jul 4;8(27):44917-44943. (PMID: 28388544)
J Exp Neurosci. 2019 Aug 07;13:1179069519868224. (PMID: 31431802)
Glycobiology. 1992 Feb;2(1):49-56. (PMID: 1550989)
Cancer Res. 2013 Sep 1;73(17):5544-55. (PMID: 23867475)
Acta Pharmacol Sin. 2009 Jul;30(7):1039-45. (PMID: 19483716)
Cancer Res. 2001 May 1;61(9):3806-9. (PMID: 11325856)
Oncotarget. 2016 Aug 9;7(32):51955-51964. (PMID: 27340870)
J Cancer Res Clin Oncol. 2011 Jan;137(1):131-7. (PMID: 20349085)
Glycobiology. 1999 Oct;9(10):1003-8. (PMID: 10521536)
Mol Cell Proteomics. 2012 Dec;11(12):1913-23. (PMID: 23023295)
Clin Transl Oncol. 2018 Sep;20(9):1175-1184. (PMID: 29423671)
Cancer Metastasis Rev. 2012 Dec;31(3-4):501-18. (PMID: 22699311)
OMICS. 2013 Oct;17(10):510-8. (PMID: 23895273)
Cancer Res. 2005 Apr 15;65(8):3025-9. (PMID: 15833827)
Nucleic Acids Res. 2019 Jan 8;47(D1):D100-D105. (PMID: 30445619)
Nature. 2009 Nov 19;462(7271):315-22. (PMID: 19829295)
Oncogene. 1991 Sep;6(9):1575-82. (PMID: 1681491)
J Biol Chem. 2018 Jan 19;293(3):984-994. (PMID: 29191829)
Cancer Discov. 2012 May;2(5):401-4. (PMID: 22588877)
Proc Natl Acad Sci U S A. 2014 Aug 26;111(34):12426-31. (PMID: 25097266)
Cancer Res. 2017 Aug 15;77(16):4414-4425. (PMID: 28646020)
Oncol Rep. 2018 Nov;40(5):2997-3005. (PMID: 30226606)
Nat Commun. 2013;4:2126. (PMID: 23839242)
J Clin Invest. 2014 Apr;124(4):1636-45. (PMID: 24590290)
Sci Rep. 2018 Jun 22;8(1):9513. (PMID: 29934500)
Genes Chromosomes Cancer. 1997 Dec;20(4):320-8. (PMID: 9408747)
Arch Gynecol Obstet. 2017 Mar;295(3):569-576. (PMID: 28154920)
Nature. 2015 Feb 19;518(7539):344-9. (PMID: 25693565)
Nature. 2014 Jul 10;511(7508):246-50. (PMID: 24909994)
J Biosci. 2012 Jun;37(2):259-67. (PMID: 22581331)
Stem Cells Transl Med. 2013 Aug;2(8):579-83. (PMID: 23817132)
Cell Signal. 2013 May;25(5):1264-71. (PMID: 23416461)
Eur J Biochem. 2004 Sep;271(18):3623-34. (PMID: 15355339)
Mol Ther. 2004 Dec;10(6):1032-42. (PMID: 15564135)
J Ovarian Res. 2008 Oct 01;1(1):3. (PMID: 19014651)
J Biol Chem. 2014 Dec 12;289(50):34627-41. (PMID: 25344606)
Cell Signal. 2013 Dec;25(12):2734-42. (PMID: 24036214)
Cancer Res. 2016 Jul 1;76(13):3978-88. (PMID: 27216178)
Nature. 2013 Dec 12;504(7479):306-310. (PMID: 24213634)
Hum Pathol. 2012 Sep;43(9):1405-12. (PMID: 22401770)
Radiat Oncol. 2012 Mar 27;7:47. (PMID: 22449099)
Stem Cell Reports. 2017 Aug 8;9(2):429-437. (PMID: 28793245)
Neoplasia. 2014 Mar;16(3):193-206, 206.e19-25. (PMID: 24726753)
Cell Res. 2016 Feb;26(2):171-89. (PMID: 26809499)
Glycobiology. 1990 Sep;1(1):25-31. (PMID: 1983783)
Oncol Lett. 2019 Aug;18(2):983-989. (PMID: 31423157)
Genes Dev. 2003 Jan 1;17(1):126-40. (PMID: 12514105)
Sci Signal. 2013 Apr 02;6(269):pl1. (PMID: 23550210)
Clin Transl Med. 2014 Jul 04;3:19. (PMID: 25114775)
J Biol Chem. 2018 Feb 2;293(5):1610-1622. (PMID: 29233887)
Molecules. 2015 Apr 24;20(5):7509-27. (PMID: 25919275)
PLoS One. 2014 Sep 17;9(9):e103988. (PMID: 25230021)
J Biol Chem. 2011 Jul 1;286(26):22982-90. (PMID: 21550977)
Int J Cancer. 2000 Oct 1;88(1):58-65. (PMID: 10962440)
Oncogene. 2003 Oct 16;22(46):7137-45. (PMID: 14562042)
J Ovarian Res. 2018 Feb 05;11(1):12. (PMID: 29402301)
World J Stem Cells. 2014 Jul 26;6(3):305-11. (PMID: 25126380)
Int J Biochem Cell Biol. 2010 Mar;42(3):421-4. (PMID: 19733254)
Glycobiology. 2018 Nov 1;28(11):898-903. (PMID: 30016515)
Cancer Res. 2013 Apr 1;73(7):2368-78. (PMID: 23358684)
J Thorac Oncol. 2008 Mar;3(3):212-5. (PMID: 18317062)
Int J Mol Sci. 2017 Oct 18;18(10):null. (PMID: 29057791)
Adv Biol Regul. 2016 Jan;60:47-63. (PMID: 26754874)
FEBS J. 2017 Sep;284(17):2705-2731. (PMID: 28317270)
Cancer Genet Cytogenet. 2010 Oct 15;202(2):82-93. (PMID: 20875870)
Cancer Cell. 2014 Dec 8;26(6):863-879. (PMID: 25490449)
Front Biosci (Elite Ed). 2012 Jan 01;4:499-515. (PMID: 22201891)

P30AI027767 United States NH NIH HHS; P30AR048311 United States NH NIH HHS; R01 NS104339 United States NH NIH HHS; R01 CA225177 United States CA NCI NIH HHS; T32 GM008111 United States GM NIGMS NIH HHS; R01 CA225177 United States NH NIH HHS

Keywords: 3q26 amplicon; Cancer stem cells; Ovarian cancer; ST6Gal-I; Sialic acid; Sox2

0 (Antigens, CD)
0 (SOX2 protein, human)
0 (SOXB1 Transcription Factors)
EC 2.4.- (Glycosyltransferases)
EC 2.4.99.- (Sialyltransferases)
EC 2.4.99.1 (ST6GAL1 protein, human)

Date Created: 20191016 Date Completed: 20200224 Latest Revision: 20200224

20240628

PMC6792265

10.1186/s13048-019-0574-5

31610800