Liver cancer initiation is controlled by AP-1 through SIRT6-dependent inhibition of survivin

Min, Lihua; Ji, Yuan; Bakiri, Latifa; Qiu, Zhixin; Cen, Jin; Chen, Xiaotao; Chen, Lingli; Scheuch, Harald; Zheng, Hao; Qin, Lun–Xiu; Zatloukal, Kurt; Hui, Lijian; Wagner, Erwin F.

doi:10.1038/ncb2590

Cited by 223 publications

(200 citation statements)

References 39 publications

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“…The increase in SIRT6 impairs cancer development by targeting the anti-apoptotic activity of survivin. Min et al 10 identified in human dysplastic liver nodules a specific expression pattern characterized by increased c-Jun-survivin and reduced cFos-SIRT6 level. In hepatocellular carcinoma (HCC), Bhardwaj et al 11 found that SIRT6 acts as a tumor suppressor because it deacetylates nuclear pyruvate kinase M2 (PKM2) inhibiting cell proliferation and tumorigenesis via PKM2.…”

Section: Sirt6 As a Tumor Suppressormentioning

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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Section: Sirt6 As a Tumor Suppressormentioning

confidence: 99%

The role of SIRT6 in tumors

2017

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“…c-Fos is able to induce transcription of the Sirt6 gene; the sirtuin in turn represses survivin via NF-κB. The significance of apoptotic resistance regulation by AP-1-SIRT6 signalling in the survival of pre-neoplastic lesions is further strengthened by the observation that both display specific expression patterns in pathological tissue samples [134].…”

Section: Transcriptional and Post-transcriptional Regulators As Sirtumentioning

confidence: 99%

Sirtuins and their interactions with transcription factors and poly(ADP-ribose) polymerases

Jęśko¹,

Strosznajder²

2016

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A b s t r a c tSirtuins vast number of targets in many cellular compartments, and some display additional enzymatic activities including mono(ADP-ribosyl)ation. SIRTs interact with multiple signalling proteins, transcription factors and enzymes including p53, FOXOs (forkhead box subgroup O), PPARs (peroxisome proliferator-activated receptors), NF-κB, and DNA-PK (DNA-dependent protein kinase). Sirtuins also interact extensively with the family of poly(ADPribose) polymerases (PARPs), a crucial and widespread class of NAD

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“…Previous studies have indicated that SIRT6 serves important roles in the development of cancer: SIRT6 expression is downregulated in a variety of types of cancer, including hepatic and breast cancer, and head and neck squamous cell carcinoma (9)(10)(11). Downregulation of SIRT6 is positively correlated with poor prognosis and low tumor-free survival rates in CRC and pancreatic ductal adenocarcinoma (12,13).…”

Section: Introductionmentioning

confidence: 99%

SIRT6 inhibits colorectal cancer stem cell proliferation by targeting CDC25A

Liu

et al. 2018

Oncol Lett

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Abstract. Silent information regulator 6 (SIRT6) is broadly considered as a tumor suppressor due to its function in the suppression of oncogene expression. However, the role of SIRT6 in colorectal cancer stem cells (CSCs) remains uncharacterized. In the present study, it was demonstrated that SIRT6 expression was reduced in colorectal CSCs. Overexpression of SIRT6 in colorectal CSCs did not induce cell apoptosis. However, SIRT6 significantly inhibited cell proliferation, colony formation and induced G0/G1 phase arrest in colorectal CSCs. In addition, SIRT6 repressed the expression of cell division cycle 25A (CDC25A), an oncogenic phosphatase. Chromatin immunoprecipitation experiments indicated that SIRT6 directly bound to the CDC25A promoter and decreased the acetylation level of histone H3 lysine 9. Altogether, these data indicated that SIRT6 inhibits colorectal cancer stem cell proliferation by targeting CDC25A.

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Liver cancer initiation is controlled by AP-1 through SIRT6-dependent inhibition of survivin

Cited by 223 publications

References 39 publications

The role of SIRT6 in tumors

The role of SIRT6 in tumors

Sirtuins and their interactions with transcription factors and poly(ADP-ribose) polymerases

SIRT6 inhibits colorectal cancer stem cell proliferation by targeting CDC25A

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