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

Sirtuin-4 (SIRT4), a therapeutic target with oncogenic and tumor-suppressive activity in cancer

“… 42 , 47 Moreover, RT-PCR analysis of mRNA extracted from human tissue demonstrated that SIRT4 mRNA levels in colon, 45 breast, 49 endometrial, 50 and esophageal cancers were reduced. 48 Decreased SIRT4 protein levels in gastric, colon, liver, lung, and esophageal cancer tissues were associated with worse pathological grading and other clinicopathological parameters. 43 , 45 , 46 , 51 , 52 At the same time, reduced SIRT4 protein levels correlated with poor prognosis in colon, lung, and esophageal cancer.…”

“… 43 , 46 Knockdown of SIRT4 increased the migration ability of KYSE170, H1299, and A549 cells. 43 , 48 In vivo studies in nude mice have shown that knockout of SIRT4 in mouse embryonic fibroblast cells forms larger tumors. 42 , 45 , 47 Moreover, SIRT4 knockout mice spontaneously develop lung cancer, liver cancer, breast cancer, and lymphomas.…”

“… 43 , 45 , 46 , 51 , 52 At the same time, reduced SIRT4 protein levels correlated with poor prognosis in colon, lung, and esophageal cancer. 43 , 45 , 46 , 48 …”

The Roles of Sirtuin Family Proteins in Cancer Progression

“…Apoptosis NSCLC [40] P53 CCA [41] MYC Metastasis HCC [42,43] AKT/GSK3β/β-catenin Axis GC [44] Tumorigenesis BC [45] Slug HCC [39] APC, CDC20 BC [39] APC, CDC20 SIRT3 Viability BLC [46] P53 PC [47] MYC; PI3K/AKT pathway CRC [48] AKT/PTEN NSCLC [49] Bax/Bcl-2, P53 HCC [50] PI3K/AKT pathway PDC [51] Apoptosis NSCLC [49] Bax/Bcl-2, P53 OSCC [52] RIP Leukemia [53] AKT, Bax/Bcl-2 Metastasis CRC [48] AKT/PTEN HCC [50] PI3K/AKT pathway PDC [51] PC [54] FOXO3A, Wnt/β-catenin pathway OC [55] Twist [57] ERK/Drp1 Axis ESCC [58] GDH CRC [59] GC [60] Apoptosis Metastasis NSCLC [57] ERK/Drp1 Axis ESCC [58] GDH CRC [59] E-cadherin GC [60] E-cadherin [72] COX-2, AKT, AMPK CRC [73] PTEN/AKT signaling ACC [74] NF-κB signaling GBM [75] JAK2/STAT3 pathway Apoptosis CRC [73] PTEN/AKT signaling HCC [70] Bax GBM [75] AK2/STAT3 pathway FSA [76] NF-κB signaling HCC [77,78] ERK1/2 pathway CC [76] NF-κB signaling Metastasis HCC [71,79] PKM2 CRC…”

The Current State of NAD+‐Dependent Histone Deacetylases (Sirtuins) as Novel Therapeutic Targets

“…Sirt4‐mediated deacetylation has been linked to cell aging and proliferation as well as the regulation of lipid metabolism and ATP homeostasis . Furthermore, Sirt4 has been identified as a tumor suppressor in colorectal cancer, esophageal squamous cell carcinoma, and Myc‐induced B‐cell lymphoma . A novel catalytic function attributed to Sirt4 is to act as a lipoamidase regulating the activity of pyruvate dehydrogenase complex (PDH), a protein complex critical for the production of acetyl‐CoA …”