title: GalNAc-T4 putatively modulates the estrogen regulatory network through FOXA1 glycosylation in human breast cancer cells.
abstract: GALNT4 belongs to a family of N-acetylgalactosaminyltransferases, which catalyze the transfer of GalNAc to Serine or Threonine residues in the initial step of mucin-type O-linked protein glycosylation. This glycosylation type is the most complex post-translational modification of proteins, playing important roles during cellular differentiation and in pathological disorders. Most of the breast cancer subtypes are estrogen receptor positive, and hence, the estrogen pathway represents a key regulatory network. We investigated the expression of GalNAc-T4 in a panel of mammary epithelial cell lines and found its expression is associated with the estrogen status of the cells. FOXA1, a key transcription factor, functions to promote estrogen responsive gene expression by acting as a cofactor to estrogen receptor alpha (ERα), but all the aspects of this regulatory mechanism are not fully explored. This study found that knockdown of GALNT4 expression in human breast cancer cells attenuated the protein expression of ERα, FOXA1, and Cyclin D1. Further, our immunoprecipitation assays depicted the possibility of FOXA1 to undergo O-GalNAc modifications with a decrease of GalNAc residues in the GALNT4 knockdown cells and also impairment in the FOXA1-ERα association. Rescuing GALNT4 expression could restore the interaction as well as the glycosylation of FOXA1. Together, these findings suggest a key role for GalNAc-T4 in the estrogen pathway through FOXA1 glycosylation.
authors.affiliation: Department of Biochemistry, Institute of Glycobiology, Dalian Medical University, 9 South Lvshun Road Western Section, Dalian, 116044, China.
authors.forename: Bachir
authors.initials: B
authors.lastname: Niang
authors.affiliation: Department of Biochemistry, Institute of Glycobiology, Dalian Medical University, 9 South Lvshun Road Western Section, Dalian, 116044, China.
authors.forename: Liyuan
authors.initials: L
authors.lastname: Jin
authors.affiliation: Department of Biochemistry, Institute of Glycobiology, Dalian Medical University, 9 South Lvshun Road Western Section, Dalian, 116044, China.
authors.forename: Xixi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Biochemistry, Institute of Glycobiology, Dalian Medical University, 9 South Lvshun Road Western Section, Dalian, 116044, China.
authors.forename: Xiaohan
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Biochemistry, Institute of Glycobiology, Dalian Medical University, 9 South Lvshun Road Western Section, Dalian, 116044, China.
authors.forename: Hongshuo
authors.initials: H
authors.lastname: Zhang
authors.affiliation: School of Life Science and Medicine, Dalian University of Technology, 2 Linggong Road, Dalian, 116024, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Department of Biochemistry, Institute of Glycobiology, Dalian Medical University, 9 South Lvshun Road Western Section, Dalian, 116044, China.
authors.forename: Arshad Ahmed
authors.initials: AA
authors.lastname: Padhiar
authors.affiliation: National Glycoengineering Research Center and State Key Laboratory of Microbial Technology, Shandong University, Jinan, 250100, China.
authors.forename: Min
authors.initials: M
authors.lastname: Xiao
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, 303 E. Chicago Ave, Chicago, IL, 60611, USA.
authors.forename: Deyu
authors.initials: D
authors.lastname: Fang
authors.affiliation: Department of Biochemistry, Institute of Glycobiology, Dalian Medical University, 9 South Lvshun Road Western Section, Dalian, 116044, China. jnzhang@dlut.edu.cn.|School of Life Science and Medicine, Dalian University of Technology, 2 Linggong Road, Dalian, 116024, China. jnzhang@dlut.edu.cn.
authors.forename: Jianing
authors.initials: J
authors.lastname: Zhang
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D055785:Gene Knockdown Techniques; D006031:Glycosylation; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000378:metabolism*; D006801:Humans; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics / Q000502:physiology*; D000097763:Polypeptide N-acetylgalactosaminyltransferase
chemical_list: D047628:Estrogen Receptor alpha; D004967:Estrogens; D051541:Hepatocyte Nuclear Factor 3-alpha; D017350:N-Acetylgalactosaminyltransferases; D000097763:Polypeptide N-acetylgalactosaminyltransferase; C496499:FOXA1 protein, human
keywords: ERα; FOXA1; GALNT4; O-Glycosylation; Vicia Villosa Lectin (VVL)