title: GalNAc-T14 promotes metastasis through Wnt dependent HOXB9 expression in lung adenocarcinoma.
abstract: While metastasis, the main cause of lung cancer-related death, has been extensively studied, the underlying molecular mechanism remains unclear. A previous clinicogenomic study revealed that expression of N-acetylgalactosaminyltransferase (GalNAc-T14), is highly inversely correlated with recurrence-free survival in those with non-small cell lung cancer (NSCLC). However, the underlying molecular mechanism(s) has not been determined. Here, we showed that GalNAc-T14 expression was positively associated with the invasive phenotype. Microarray and biochemical analyses revealed that HOXB9, the expression of which was increased in a GalNAc-T14-dependent manner, played an important role in metastasis. GalNAc-T14 increased the sensitivity of the WNT response and increased the stability of the β-catenin protein, leading to induced expression of HOXB9 and acquisition of an invasive phenotype. Pharmacological inhibition of β-catenin in GalNAc-T14-expressing cancer cells suppressed HOXB9 expression and invasion. A meta-analysis of clinical genomics data revealed that expression of GalNAc-T14 or HOXB9 was strongly correlated with reduced recurrence-free survival and increased hazard risk, suggesting that targeting β-catenin within the GalNAc-T14/WNT/HOXB9 axis may be a novel therapeutic approach to inhibit metastasis in NSCLC.
authors.affiliation: College of Natural Sciences, Department of Life Sciences, Sogang University, Seoul, Republic of Korea.
authors.forename: Ok-Seon
authors.initials: OS
authors.lastname: Kwon
authors.affiliation: Laboratory of Cancer Genomics and Molecular Pathology, Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Republic of Korea.
authors.forename: Ensel
authors.initials: E
authors.lastname: Oh
authors.affiliation: College of Natural Sciences, Department of Life Sciences, Sogang University, Seoul, Republic of Korea.
authors.forename: Jeong-Rak
authors.initials: JR
authors.lastname: Park
authors.affiliation: College of Natural Sciences, Department of Life Sciences, Sogang University, Seoul, Republic of Korea.
authors.forename: Ji-Seon
authors.initials: JS
authors.lastname: Lee
authors.affiliation: College of Natural Sciences, Department of Life Sciences, Sogang University, Seoul, Republic of Korea.
authors.forename: Gab-Yong
authors.initials: GY
authors.lastname: Bae
authors.affiliation: Department of Brain and Cognitive Sciences, DGIST, Daegyu, Republic of Korea.
authors.forename: Jae-Hyung
authors.initials: JH
authors.lastname: Koo
authors.affiliation: Department of Pharmacology, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Hyongbum
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Pathology, Samsung Medical Center, Sungkyunkwan University, School of Medicine, Seoul, Republic of Korea.
authors.forename: Yoon L
authors.initials: YL
authors.lastname: Choi
authors.affiliation: Department of Thoracic Surgery, Samsung Medical Center, Sungkyunkwan University, School of Medicine, Seoul, Republic of Korea.
authors.forename: Young Soo
authors.initials: YS
authors.lastname: Choi
authors.affiliation: Department of Thoracic Surgery, Samsung Medical Center, Sungkyunkwan University, School of Medicine, Seoul, Republic of Korea.
authors.forename: Jhingook
authors.initials: J
authors.lastname: Kim
authors.affiliation: College of Natural Sciences, Department of Life Sciences, Sogang University, Seoul, Republic of Korea.
authors.forename: Hyuk-Jin
authors.initials: HJ
authors.lastname: Cha
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy; D000077192:Adenocarcinoma of Lung; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D030541:Databases, Genetic; D018572:Disease-Free Survival; D020869:Gene Expression Profiling / Q000379:methods; D064593:Heterografts; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D055550:Protein Stability; D011744:Pyrimidinones / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D016896:Treatment Outcome; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; C495270:CTNNB1 protein, human; C491257:HOXB9 protein, human; D018398:Homeodomain Proteins; C492448:ICG 001; D011744:Pyrimidinones; D051176:beta Catenin; D017350:N-Acetylgalactosaminyltransferases; C471038:UDP-N-acetyl-D-galactosamine polypeptide N-acetylgalactosaminyltransferase 14, human
keywords: GalNAc-T14; HOXB9; WNT/TCF pathway; invasion; metastasis