USP10 Antagonizes c-Myc Transcriptional Activation through SIRT6 Stabilization to Suppress Tumor Formation

Lin, Zhenghong; Yang, Hee‐Young; Tan, Chiu C.; Li, Jinping; Liu, Zhaojian; Qiu, Quan; Kong, Sinyi; Ye, Junsheng; Gao, Beixue; Fang, Deyu

doi:10.1016/j.celrep.2013.11.029

Cited by 165 publications

(140 citation statements)

References 37 publications

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“…Moreover, USP10 could stabilize Beclin1 by inhibiting its ubiquitination, which reciprocally stabilizes USP10 and promotes p53-dependent apoptosis (46). A recent report found that USP10 could interact with and deubiquitinates SIRT6, which enhanced SIRT6 stability and resulted in SIRT6/p53-dependent suppression of c-Myc oncogenic activity (47). All of these studies indicate that USP10 may play a tumor-suppressive role by deubiquitinating and stabilizing critical tumor suppressors.…”

Section: Discussionmentioning

confidence: 99%

TRAF Family Member-associated NF-κB Activator (TANK) Inhibits Genotoxic Nuclear Factor κB Activation by Facilitating Deubiquitinase USP10-dependent Deubiquitination of TRAF6 Ligase

Wang

Huang

Xiao

et al. 2015

Journal of Biological Chemistry

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Background: TANK has been shown to promote deubiquitination of TRAFs, but the mechanism involved is unclear. Results: TANK associates with MCPIP1 and USP10, thereby diminishing TRAF6 ubiquitination, which inhibits NF-B activation by genotoxic stress and IL-1R/TLR activation. Conclusion:The deubiquitinating activity of TANK is achieved by its association with USP10. Significance: Modulating TANK may enhance cancer cell sensitivity to chemotherapy.

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Section: Discussionmentioning

confidence: 99%

TRAF Family Member-associated NF-κB Activator (TANK) Inhibits Genotoxic Nuclear Factor κB Activation by Facilitating Deubiquitinase USP10-dependent Deubiquitination of TRAF6 Ligase

Wang

Huang

Xiao

et al. 2015

Journal of Biological Chemistry

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“…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 dysregulated USP10 function promotes tumorigenesis through SIRT6 degradation. Lin et al also showed an important reduction in USP10 (a deubiquitinase protein) and SIRT6 expression.…”

Section: Sirt6 As a Tumor Suppressormentioning

confidence: 99%

Section: Sirt6 As a Tumor Suppressormentioning

confidence: 99%

“…Indeed, the downregulation of USP10 triggers SIRT6 instability and negatively controls the transcriptional activity of the c-Myc oncogene that inhibits cell-cycle progression, cancer cell growth, and tumor formation. 9 In liver cancer, the SIRT6 suppression is regulated by the c-Jun/c-Fos pathway:10 c-Fos induces SIRT6 transcription and represses survivin by reducing histone H3K9 acetylation and NF-κB activation. The increase in SIRT6 impairs cancer development by targeting the anti-apoptotic activity of survivin.…”

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confidence: 99%

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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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“…SIRT6 is localized in the nucleus [1] and has two types of enzymatic activities: mono-adenosine diphosphate ribosyltransferase [3] and deacetylase [4] activities, both of which are dependent on nicotinamide adenine dinucleotide [5]. SIRT6 regulates various cellular processes, including telomere maintenance, repair of damaged DNA, aging, immunity, and glucose homeostasis, and is important in cancer [3,[6][7][8][9]. SIRT6 deficiency in mice leads to developmental and metabolic abnormalities as well as a shorter lifespan, whereas SIRT6 activation is associated with a longer lifespan [8].…”

Section: Introductionmentioning

confidence: 99%

Docosahexaenoic Acid Induces Cell Death through Downregulation of Hedgehog Signaling via Surt6 Activation in Human EGFR Mutant Non-Small Cell Lung Cancer

Jeong¹,

Jing²,

Shin³

et al. 2017

Preprint

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Omega-3 polyunsaturated fatty acids (ω3-PUFAs), including docosahexaenoic acid (DHA), have been shown to exert anticancer effects by inducing apoptotic cell death. However, the mechanism for DHA-induced cell death in lung cancer is not fully understood. Here, we show that DHA induces apoptosis in two human EGFR mutant non-small cell lung cancer (NSCLC) cell lines, and that DHA-induced cell death is accompanied by SIRT6 activation and attenuated Hedgehog (Hh) signaling. Knockdown of SIRT6 using siRNAs inhibited DHA-induced apoptosis, whereas SIRT6 overexpression increased apoptotic cell death. DHA-induced SIRT6 activation was

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USP10 Antagonizes c-Myc Transcriptional Activation through SIRT6 Stabilization to Suppress Tumor Formation

Cited by 165 publications

References 37 publications

TRAF Family Member-associated NF-κB Activator (TANK) Inhibits Genotoxic Nuclear Factor κB Activation by Facilitating Deubiquitinase USP10-dependent Deubiquitination of TRAF6 Ligase

TRAF Family Member-associated NF-κB Activator (TANK) Inhibits Genotoxic Nuclear Factor κB Activation by Facilitating Deubiquitinase USP10-dependent Deubiquitination of TRAF6 Ligase

The role of SIRT6 in tumors

Docosahexaenoic Acid Induces Cell Death through Downregulation of Hedgehog Signaling via Surt6 Activation in Human EGFR Mutant Non-Small Cell Lung Cancer

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