Downregulation of SIRT4 expression is associated with poor prognosis in esophageal squamous cell carcinoma

Yujiro Nakahara, Makoto Yamasaki, Genta Sawada, Yasuhiro Miyazaki, Tomoki Makino, Tsuyoshi Takahashi, Yukinori Kurokawa, Kiyokazu Nakajima, Shuji Takiguchi, Koshi Mimori, Masaki Mori, Yuichiro Doki

Research output: Contribution to journalArticlepeer-review

24 Citations (Scopus)

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. Conclusion: SIRT4 is a potential prognostic biomarker in ESCC.

Original languageEnglish
Pages (from-to)347-355
Number of pages9
JournalOncology (Switzerland)
Volume90
Issue number6
DOIs
Publication statusPublished - Jun 14 2016

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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