title: SMYD3 stimulates EZR and LOXL2 transcription to enhance proliferation, migration, and invasion in esophageal squamous cell carcinoma.
abstract: Epigenetic alterations, including DNA methylation and histone modifications, are involved in the regulation of cancer initiation and progression. SET and MYND domain-containing protein 3 (SMYD3), a methyltransferase, plays an important role in transcriptional regulation during human cancer progression. However, SMYD3 expression and its function in esophageal squamous cell carcinoma (ESCC) remain unknown. In this study, SMYD3 expression was studied by immunohistochemistry in a tumor tissue microarray from 131 cases of ESCC patients. Statistical analysis showed that overall survival of patients with high SMYD3 expressing in primary tumors was significantly lower than that of patients with low SMYD3-expressing tumors (P = .008, log-rank test). Increased expression of SMYD3 was found to be associated with lymph node metastasis in ESCC (P = .036) and was an independent prognostic factor for poor overall survival (P = .025). RNAi-mediated knockdown of SMYD3 suppressed ESCC cell proliferation, migration, and invasion in vitro and inhibited local tumor invasion in vivo. SMYD3 regulated transcription of EZR and LOXL2 by directly binding to the sequences of the promoter regions of these target genes, as demonstrated by a chromatin immunoprecipitation assay. Immunohistochemical staining of ESCC tissues also confirmed that protein levels of EZR and LOXL2 positively correlated with SMYD3 expression, and the Spearman correlation coefficients (rs) were 0.78 (n = 81; P < .01) and 0.637 (n = 103; P < .01), respectively. These results indicate that SMYD3 enhances tumorigenicity in ESCC through enhancing transcription of genes involved in proliferation, migration, and invasion.
authors.affiliation: The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, Guangdong, PR China; Institute of Oncologic Pathology, Shantou University Medical College, Shantou 515041, Guangdong, PR China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, Guangdong, PR China; Institute of Oncologic Pathology, Shantou University Medical College, Shantou 515041, Guangdong, PR China.
authors.forename: Meng-Xiao
authors.initials: MX
authors.lastname: Zhu
authors.affiliation: The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, Guangdong, PR China; Institute of Oncologic Pathology, Shantou University Medical College, Shantou 515041, Guangdong, PR China.
authors.forename: Xiao-Dan
authors.initials: XD
authors.lastname: Zhang
authors.affiliation: The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, Guangdong, PR China; Institute of Oncologic Pathology, Shantou University Medical College, Shantou 515041, Guangdong, PR China.
authors.forename: Xiu-E
authors.initials: XE
authors.lastname: Xu
authors.affiliation: Departments of Oncology Surgery, Shantou Central Hospital, Affiliated Shantou Hospital of Sun Yat-Sen University, Shantou 515041, Guangdong, PR China.
authors.forename: Zhi-Yong
authors.initials: ZY
authors.lastname: Wu
authors.affiliation: The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, Guangdong, PR China; Institute of Oncologic Pathology, Shantou University Medical College, Shantou 515041, Guangdong, PR China.
authors.forename: Lian-Di
authors.initials: LD
authors.lastname: Liao
authors.affiliation: The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, Guangdong, PR China; Institute of Oncologic Pathology, Shantou University Medical College, Shantou 515041, Guangdong, PR China.
authors.forename: Li-Yan
authors.initials: LY
authors.lastname: Li
authors.affiliation: The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, Guangdong, PR China; Experimental Animal Center, Shantou University Medical College, Shantou 515041, Guangdong, PR China.
authors.forename: Yang-Min
authors.initials: YM
authors.lastname: Xie
authors.affiliation: The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, Guangdong, PR China; Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, Guangdong, PR China.
authors.forename: Jian-Yi
authors.initials: JY
authors.lastname: Wu
authors.affiliation: The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, Guangdong, PR China; Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, Guangdong, PR China.
authors.forename: Hai-Ying
authors.initials: HY
authors.lastname: Zou
authors.affiliation: The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, Guangdong, PR China; Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, Guangdong, PR China.
authors.forename: Jian-Jun
authors.initials: JJ
authors.lastname: Xie
authors.affiliation: The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, Guangdong, PR China; Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, Guangdong, PR China. Electronic address: nmli@stu.edu.cn.
authors.forename: En-Min
authors.initials: EM
authors.lastname: Li
authors.affiliation: The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, Guangdong, PR China; Institute of Oncologic Pathology, Shantou University Medical College, Shantou 515041, Guangdong, PR China. Electronic address: lyxu@stu.edu.cn.
authors.forename: Li-Yan
authors.initials: LY
authors.lastname: Xu
mesh_terms: D000594:Amino Acid Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000556:secondary; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D004938:Esophageal Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D034622:RNA Interference; D012189:Retrospective Studies; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D000099149:Ezrin
chemical_list: D000594:Amino Acid Oxidoreductases; D003598:Cytoskeletal Proteins; D011495:Histone-Lysine N-Methyltransferase; D000099149:Ezrin; C119091:LOXL2 protein, human; C506278:SMYD3 protein, human
keywords: ESCC; EZR; Epigenetics; LOXL2; SMYD3; Target genes; Transcriptional regulation