Reciprocal Regulation between SIRT6 and miR-122 Controls Liver Metabolism and Predicts Hepatocarcinoma Prognosis

Elhanati, Sivan; Ben‐Hamo, Rotem; Kanfi, Yariv; Varvak, Alexander; Glazz, Renana; Lerrer, Batia; Efroni, Sol; Cohen, Haim Y.

doi:10.1016/j.celrep.2015.12.023

Cited by 73 publications

(72 citation statements)

References 40 publications

(53 reference statements)

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“…Recently, a new study has suggested that many of these functions of SIRT6 may be impacted by a complex interplay with miR-122, the most abundant hepatic microRNA [76]. Like SIRT6 overexpressing mice, miR-122-deficient mice have improved lipid profiles and are resistant to pathologies of diet-induced obesity [66, 77].…”

Section: Regulation Of Glucose and Lipid Homeostasis In Metabolism Anmentioning

confidence: 99%

“…Like SIRT6 overexpressing mice, miR-122-deficient mice have improved lipid profiles and are resistant to pathologies of diet-induced obesity [66, 77]. Elhanati et al now provide evidence that SIRT6 and mi-R122 negatively regulate each other and have opposite effects on fatty acid metabolism and expression of β-oxidation regulatory enzymes [76]. These findings suggest that modulation of miR-122 levels could be useful for treatment of metabolic disorders associated with reduced SIRT6 activity in aging, obesity, or diabetes [45, 69, 78].…”

Section: Regulation Of Glucose and Lipid Homeostasis In Metabolism Anmentioning

confidence: 99%

“…These findings suggest that modulation of miR-122 levels could be useful for treatment of metabolic disorders associated with reduced SIRT6 activity in aging, obesity, or diabetes [45, 69, 78]. In addition, the functional interplay between SIRT6 and miR-122 in lipid metabolism may have important pathological effects in hepatocellular carcinomas (HCC), because a strong negative correlation between their expression is predictive of poor survival in HCC patients [76]. …”

Section: Regulation Of Glucose and Lipid Homeostasis In Metabolism Anmentioning

confidence: 99%

See 2 more Smart Citations

SIRT6: Novel Mechanisms and Links to Aging and Disease

Tasselli

Zheng

Chua

2017

Trends in Endocrinology & Metabolism

221

201

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SIRT6, a member of the Sirtuin family of NAD+-dependent enzymes, has established roles in chromatin signaling and genome maintenance. Through these functions, SIRT6 protects against aging-associated pathologies including metabolic disease and cancer, and can promote longevity in mice. Research from the last few years has revealed that SIRT6 is a complex enzyme with multiple substrates and catalytic activities, and uncovered novel SIRT6 functions in maintenance of organismal health span. Here, we review these new discoveries and models of SIRT6 biology in four areas: heterochromatin stabilization and silencing, stem cell biology, cancer initiation and progression, and regulation of metabolic homeostasis. We discuss possible implications of these findings for therapeutic interventions in aging and aging-related disease processes.

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Section: Regulation Of Glucose and Lipid Homeostasis In Metabolism Anmentioning

confidence: 99%

Section: Regulation Of Glucose and Lipid Homeostasis In Metabolism Anmentioning

confidence: 99%

Section: Regulation Of Glucose and Lipid Homeostasis In Metabolism Anmentioning

confidence: 99%

See 1 more Smart Citation

SIRT6: Novel Mechanisms and Links to Aging and Disease

Tasselli

Zheng

Chua

2017

Trends in Endocrinology & Metabolism

221

201

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“…As a consequence, it enhances p53 and E2F-1 chromatin accessibility thus inhibiting apoptosis. Elhanati et al 20 and Lefor et al 21 correlated SIRT6 regulation to two microRNAs (miR-) in two different cancers. At basal conditions, SIRT6 and miR-122 negatively regulate each other in HCC.…”

Section: Sirt6 As a Tumor Promotermentioning

confidence: 99%

“…The miR-122 binds SIRT6 3′ UTR and reduces its levels, while the loss of the negative correlation between SIRT6 and miR-122 expression is significantly associated with better prognosis. 20 In addition, miR-34a plays a key role during The role of SIRT6 is not well known in hematologic malignancies. In multiple myeloma (MM), SIRT6 is highly expressed as adaptive response to genomic stability, and its overexpression is associated to proliferation and poor prognosis.…”

Section: Sirt6 As a Tumor Promotermentioning

confidence: 99%

The role of SIRT6 in tumors

2017

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Dysfunctional DNA-damage response and consequent genomic instability play a pivotal role in the initiation and progression of both solid and hematologic tumors. Preservation of DNA integrity is, in fact, a key cellular function, hence several mechanisms that repair the damaged DNA need to be studied. Recent studies have focused on key players that are able to improve the DNA repair and thus may act as targets for new therapeutic approaches.Several data have been obtained on overexpression and hyperactivity of Sirtuins (SIRTs), a family of proteins with deacylase or mono-adenosine diphosphate (ADP)-ribosyltransferase activities that degrade nicotinamide adenine dinucleotide (NAD + ) enzymes to enable their biological processes 1 and promote longevity. 2 In mammalian cells, the Sirtuin family is composed of seven members that show different subcellular localization and functions (transcription, metabolism, fat mobilization, DNA repair, stress responses, apoptosis, tumorigenesis and aging), 3,4 and conserve the catalytic domain and the NAD + binding site. 5 In cancer and agingassociated pathways, SIRT6 is crucial since it prevents genomic instability, maintains telomere integrity, and regulates metabolic homeostasis and DNA repair. 6 SIRT6 can be considered a double-edged sword in cancer because of its dual role of both tumor suppressor and oncogene (Table 1). In healthy conditions, SIRT6 either acts as a gatekeeper of DNA repair mechanisms or regulates cell survival and proliferation. Following the DNA damage, SIRT6 triggers the apoptotic process, hence it is down-regulated in several cancers. However, in other cancers, it is up-regulated, corroborating the idea that it can also act as oncogene. SIRT6 as a tumor suppressorStudies in colorectal, breast, ovarian, hepatocellular, lung, and other tumors correlate the reduction of SIRT6 expression with tumor progression and poor clinical outcome. In the presence of DNA-damage, SIRT6 promotes apoptotic cell death, ensuring damaged cells do not proliferate. Sebastian et al. 7 demonstrated in vivo that SIRT6 deficiency favors tumor growth and invasiveness. They also showed that SIRT6 is involved in the Warburg effect, a glycolytic metabolic shift important for supporting rapid tumor growth. SIRT6 promotes both in vitro and in vivo tumor suppression through repression of hypoxia-inducible factor 1-alpha (HIF-1α) that inhibits glycolytic metabolism in cancer cells.7 Interestingly, in mouse and human pancreatic ductal adenocarcinoma (PDAC), the SIRT6 knockdown is due to repression of Myc-target oncofetal protein Lin28b that negatively regulates the let-7 family of miRNAs. 8 In detail, loss of SIRT6 triggers activation of Lin28 promoter, Myc recruitment, and consequent activation of Lin28b, the downstream let-7 target genes (HMGA2, IGF2BP1) and IGF2BP3 that accelerate the PDAC progression and metastasis. 8 In human colon cancer, Lin et al. 9 discovered the crosstalk between UPS10 and SIRT6 that regulates cell-cycle progression and proliferation, and showed that the dysregul...

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Ubiquitin‐Specific Peptidase 10 (USP10) Inhibits Hepatic Steatosis, Insulin Resistance, and Inflammation Through Sirt6

Luo

Qin²,

Zhu

et al. 2018

Hepatology

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Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, insulin resistance and inflammation, and the pathogenic mechanism of NAFLD is poorly understood. Ubiquitin-specific peptidase 10 (USP10), a member of the ubiquitin-specific protease family, is involved in environmental stress responses, tumor growth, inflammation, and cellular metabolism. However, the role of USP10 in hepatic steatosis, insulin resistance, and inflammation remains largely unexplored. USP10 expression was detected in livers of patients with NAFLD, mice with high-fat diet (HFD)-induced obesity, and genetically obese (ob/ob) mice, as well as in palmitate-induced hepatocytes. The function of USP10 in hepatic steatosis, insulin resistance, and inflammation was investigated using hepatocyte-specific USP10 deficiency or overexpression in mice induced by HFD treatment or genetic defect. The molecular mechanisms underlying USP10-regulated hepatic steatosis were further investigated in HFD-treated mice. USP10 expression was significantly decreased in the fatty livers of NAFLD patients and obese mice and in palmitate-treated hepatocytes. USP10 deficiency exacerbated the metabolic dysfunction induced by HFD treatment for 12 weeks. Conversely, USP10 overexpression significantly suppressed metabolic dysfunction in mice after HFD treatment and inhibited the development of NAFLD in ob/ob mice. Further investigation indicated that USP10 regulates hepatic steatosis by interacting with Sirt6 and inhibiting its ubiquitination and degradation. Sirt6 overexpression markedly ameliorated the effects of USP10 deficiency in hepatic steatosis, insulin resistance, and inflammation. Conversely, Sirt6 deficiency decreased the ameliorative effects of USP10 overexpression in response to HFD treatment. Conclusion: USP10 inhibits hepatic steatosis, insulin resistance, and inflammation through Sirt6.

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Reciprocal Regulation between SIRT6 and miR-122 Controls Liver Metabolism and Predicts Hepatocarcinoma Prognosis

Cited by 73 publications

References 40 publications

SIRT6: Novel Mechanisms and Links to Aging and Disease

SIRT6: Novel Mechanisms and Links to Aging and Disease

The role of SIRT6 in tumors

Ubiquitin‐Specific Peptidase 10 (USP10) Inhibits Hepatic Steatosis, Insulin Resistance, and Inflammation Through Sirt6

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