title: Downregulation of SIRT4 Expression Is Associated with Poor Prognosis in Esophageal Squamous Cell Carcinoma.
abstract: OBJECTIVE
  SIRT4, a mitochondria-localized sirtuin, represses glutamine metabolism by inhibiting glutamate dehydrogenase (GDH). The current study aimed to evaluate the clinical and biological significance of SIRT4 in esophageal squamous cell carcinoma (ESCC).
  
  
  METHODS
  The study comprised 172 patients with surgically resected ESCC in two independent cohorts. SIRT4 mRNA expression was analyzed in Cohort 1 (n = 79) and SIRT4 protein expression in Cohort 2 (n = 93). The association of SIRT4 expression with clinicopathological parameters and prognosis was assessed. Furthermore, the biological role of SIRT4 in ESCC cell lines was examined.
  
  
  RESULTS
  SIRT4 expression was not correlated with any clinicopathological parameters in both cohorts. In Cohort 1, low-SIRT4-expression cases had poorer overall survival than high-SIRT4-expression cases (p = 0.016). In Cohort 2, SIRT4-negative cases had poorer overall survival and disease-free survival than SIRT4-positive cases (p = 0.011 and 0.0026). Multivariate analysis revealed that SIRT4 expression was an independent prognostic factor for overall survival (HR = 2.06, p = 0.038). The rate of distant recurrence was significantly higher in SIRT4-negative cases than in SIRT4-positive cases (39.4 vs. 7.4%; p = 0.0023). In vitro, SIRT4 knockdown significantly increased GDH activity and promoted cell proliferation and migration.
  
  
  CONCLUSIONS
  SIRT4 is a potential prognostic biomarker in ESCC.
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan.
authors.forename: Yujiro
authors.initials: Y
authors.lastname: Nakahara
authors.forename: Makoto
authors.initials: M
authors.lastname: Yamasaki
authors.forename: Genta
authors.initials: G
authors.lastname: Sawada
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Miyazaki
authors.forename: Tomoki
authors.initials: T
authors.lastname: Makino
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Takahashi
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Kurokawa
authors.forename: Kiyokazu
authors.initials: K
authors.lastname: Nakajima
authors.forename: Shuji
authors.initials: S
authors.lastname: Takiguchi
authors.forename: Koshi
authors.initials: K
authors.lastname: Mimori
authors.forename: Masaki
authors.initials: M
authors.lastname: Mori
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Doki
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D018572:Disease-Free Survival; D015536:Down-Regulation; D004938:Esophageal Neoplasms / Q000378:metabolism* / Q000473:pathology*; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000378:metabolism; D011237:Predictive Value of Tests; D011379:Prognosis; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D024101:Mitochondrial Proteins; C525357:SIRT4 protein, human; D037761:Sirtuins