Tumour-suppressive function of SIRT4 in human colorectal cancer

Miyo, Masaaki; Yamamoto, Hirofumi; Konno, Masamitsu; Colvin, Hugh; Nishida, Naohiro; Koseki, Junichi; Kikuchi, Kôichi; Ogawa, Hisataka; Hamabe, Atsushi; Uemura, Mamoru; Nishimura, Junichi; Hata, Tsuyoshi; Takemasa, Ichiro; Mizushima, Tsunekazu; Doki, Yuichiro; Mori, Masaki; Ishii, Hideshi

doi:10.1038/bjc.2015.226

Cited by 131 publications

(110 citation statements)

References 20 publications

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“…However, it has been challenging to demonstrate whether the altered metabolite levels are merely the consequence of the disease or whether they have an active role in driving the disease process. In this study, we provide further support that deranged metabolism drives the disease process in cancer, and that this is mediated by metabolites831. Our findings are also consistent with an earlier report that IDH mutation can induce EMT through the production of D-2HG and the increased expression of ZEB1 32.…”

Section: Discussionsupporting

confidence: 92%

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Oncometabolite D-2-Hydroxyglurate Directly Induces Epithelial-Mesenchymal Transition and is Associated with Distant Metastasis in Colorectal Cancer

Colvin

Nishida

Konno

et al. 2016

Sci Rep

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Deranged metabolism is a hallmark of cancer, playing a significant role in driving the disease process. One such example is the induction of carcinogenesis by the oncometabolite D-2 hydroxyglutarate (D-2HG), which is produced by the mutated enzyme isocitrate dehydrogenase (IDH) occurring in subsets of leukaemias and brain tumours. The oncogenic property of D-2HG appears to stem from its ability to interfere with the activities of α-ketoglutarate-dependent dioxygenases, including the Jumonji family histone demethylases. Here, we find in colorectal cancer cells that even in the absence of IDH mutation, the levels of D-2HG and its enantiomer L-2HG were elevated through glutamine anaplerosis. D-2HG, but not L-2HG, increased the trimethylation of histone H3 lysine 4 of the promoter region of ZEB1, a master regulator of epithelial-mesenchymal transition (EMT), and increased the expression of the ZEB1 gene to directly induce EMT in colorectal cancer cells. EMT promotes the ability of cancer cells to invade the local tissue and enter into the bloodstream, leading to distant organ metastasis. D-2HG levels were elevated in colorectal cancer specimens, particularly in those associated with distant metastasis, supporting the observations in vitro and implicating the contribution of D-2HG in metastasis, the major cause of death in this disease.

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Section: Discussionsupporting

confidence: 92%

“…Moreover, we and others have found that deranged metabolism also drives oncogenesis6 and disease progression78, highlighting the significant role of cellular metabolism throughout the disease process and as a promising target for treatment.…”

mentioning

confidence: 77%

Oncometabolite D-2-Hydroxyglurate Directly Induces Epithelial-Mesenchymal Transition and is Associated with Distant Metastasis in Colorectal Cancer

Colvin

Nishida

Konno

et al. 2016

Sci Rep

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“…In a recent study, down-regulation of SIRT4 has been shown to be associated with poor prognosis in head and neck squamous cell carcinoma (HNSCC) patients (64). Tumor suppressor function of SIRT4 is also reported in colorectal cancer where SIRT4 has been shown to cause E-cadherin upregulation thereby suppressing the proliferation, migration and invasion through inhibition of glutamine metabolism (65). Jeong et al have shown that SIRT4 loss causes increased glutamine-dependent proliferation and stress-induced genomic instability, and SIRT4 knockout mice spontaneously develop lung tumors (66).…”

Section: Mitochondrial Sirts and Their Molecular Targets: Relevance Tmentioning

confidence: 99%

Mitochondrial Sirtuins in Cancer: Emerging Roles and Therapeutic Potential

George

Ahmad

2016

Cancer Research

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The past few decades have witnessed a furious attention of scientific community towards identifying novel molecular factors and targets which could be exploited for drug development for cancer management. One such factor is the sirtuin (SIRT) family of nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases. The role of SIRTs in cancer is extremely complex, with dichotomous functions depending on cell contexts. Mammalian SIRTs (SIRT1–7), differ in their cellular localization and biological functions. Amongst these, SIRT -3, -4, and -5 are located in the mitochondria and are being carefully investigated. These mitochondrial SIRTs (mtSIRTs) regulate multiple cellular and physiological processes, including cell cycle, gene expression, cell viability, stress response, metabolism and energy homeostasis. Recent research suggests that mtSIRTs influence tumors by regulating the metabolic state of the cell. While the research on the role of mtSIRTs in cancer is still in its infancy, studies have suggested tumor suppressor as well as tumor promoter roles for them. This review is focused on discussing an up-to-date information about the roles and functional relevance of mtSIRTs (SIRT -3, -4, -5) in cancers. We have also provided a critical discussion and our perspective on their dual roles, as tumor promoter versus tumor suppressor, in cancer.

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“…Recently, it was reported that SIRT4 negatively regulates mitochondrial glutamine metabolism via the inhibition of glutamate dehydrogenase (GDH) and has tumor-suppressive functions [8][9][10] . Currently, there are only a few reports concerning SIRT4 and prognosis in several types of cancer [8,9,11,12] .…”

Section: Downregulation Of Sirt4 Expression Is Associated With Poor Pmentioning

confidence: 99%

Downregulation of SIRT4 Expression Is Associated with Poor Prognosis in Esophageal Squamous Cell Carcinoma

et al. 2016

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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.

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Tumour-suppressive function of SIRT4 in human colorectal cancer

Cited by 131 publications

References 20 publications

Oncometabolite D-2-Hydroxyglurate Directly Induces Epithelial-Mesenchymal Transition and is Associated with Distant Metastasis in Colorectal Cancer

Oncometabolite D-2-Hydroxyglurate Directly Induces Epithelial-Mesenchymal Transition and is Associated with Distant Metastasis in Colorectal Cancer

Mitochondrial Sirtuins in Cancer: Emerging Roles and Therapeutic Potential

Downregulation of SIRT4 Expression Is Associated with Poor Prognosis in Esophageal Squamous Cell Carcinoma

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