title: Metastatic Progression of Prostate Cancer Is Mediated by Autonomous Binding of Galectin-4-O-Glycan to Cancer Cells.
abstract: Metastatic prostate cancer continues to pose a difficult therapeutic challenge. Prostate cancer progression is associated with aberrant O-glycosylation of cancer cell surface receptors, but the functional impact of such events is uncertain. Here we report spontaneous metastasis of human prostate cancer xenografts that express high levels of galectin-4 along with genetic signatures of EGFR-HER2 signaling and O-glycosylation. Galectin-4 expression in clinical specimens of prostate cancer correlated with poor patient survival. Galectin-4 binding to multiple receptor tyrosine kinases stimulated their autophosphorylation, activated expression of pERK, pAkt, fibronectin, and Twist1, and lowered expression of E-cadherin, thereby facilitating epithelial-mesenchymal transition, invasion, and metastasis. In vivo investigations established that galectin-4 expression enabled prostate cancer cells to repopulate tumors in orthotopic and heterotopic tissues. Notably, these effects of galectin-4 relied upon O-glycosylation mediated by C1GALT1, a galactosyltransferase implicated in other cancers. Parallel changes in galectin-4 and O-glycosylation triggered aberrant receptor signaling and more aggressive invasive character in prostate cancer cells, which through better survival in the circulation also contributed to the bulk cell progeny of distal tumors. Our findings establish galectin-4 and C1GALT1-mediated glycosylation in a signaling axis that is activated during prostate cancer progression, with implications for therapeutic targeting of advanced metastatic disease. Cancer Res; 76(19); 5756-67. ©2016 AACR.
authors.affiliation: Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan. Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan.
authors.forename: Chin-Hsien
authors.initials: CH
authors.lastname: Tsai
authors.affiliation: Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan. Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Sheue-Fen
authors.initials: SF
authors.lastname: Tzeng
authors.affiliation: Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Tai-Kuang
authors.initials: TK
authors.lastname: Chao
authors.affiliation: Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Chia-Yun
authors.initials: CY
authors.lastname: Tsai
authors.affiliation: Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Yu-Chih
authors.initials: YC
authors.lastname: Yang
authors.affiliation: Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan.
authors.forename: Ming-Ting
authors.initials: MT
authors.lastname: Lee
authors.affiliation: Institute of Physiology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Jiuan-Jiuan
authors.initials: JJ
authors.lastname: Hwang
authors.affiliation: School of Public Health, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Yu-Ching
authors.initials: YC
authors.lastname: Chou
authors.affiliation: Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan. Institute of Biotechnology, National Taiwan University, Taipei, Taiwan.
authors.forename: Mong-Hsun
authors.initials: MH
authors.lastname: Tsai
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan. Division of Urology, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Tai-Lung
authors.initials: TL
authors.lastname: Cha
authors.affiliation: Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan. Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan. pwhsiao@gate.sinica.edu.tw.
authors.forename: Pei-Wen
authors.initials: PW
authors.lastname: Hsiao
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005700:Galactosyltransferases / Q000502:physiology; D037541:Galectin 4 / Q000032:analysis / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D011134:Polysaccharides / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology
chemical_list: D037541:Galectin 4; D011134:Polysaccharides; C505293:C1GALT1 protein, human; D005700:Galactosyltransferases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases