Partitioning Circadian Transcription by SIRT6 Leads to Segregated Control of Cellular Metabolism

Masri, Selma; Rigor, Paul; Cervantes, Marlene; Ceglia, Nicholas; Sebastián, Carlos; Xiao, Cuiying; Roqueta‐Rivera, Manuel; Deng, Chu‐Xia; Osborne, Timothy F.; Mostoslavsky, Raúl; Baldi, Pierre; Sassone–Corsi, Paolo

doi:10.1016/j.cell.2014.06.050

Cited by 256 publications

(241 citation statements)

References 61 publications

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“…16,17 Moreover, multiple investigations have revealed that SIRT6 regulates the pathogenesis of various types of cancers, such as including hepatocellular carcinoma, breast cancer, and pancreatic cancer. [18][19][20] Molecular mechanism exploration further indicates that the diverse roles of SIRT6 in carcinogenesis are implemented through the regulation of cellular signals including ERK, Smad, and Raf/mitogen-activated extracellular signal-regulated kinase/extracellular signal-regulated kinase pathway.…”

Section: Discussionmentioning

confidence: 99%

Astragaloside IV sensitizes non–small cell lung cancer cells to gefitinib potentially via regulation of SIRT6

et al. 2017

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Astragaloside IV, the active component of Astragalus membranaceus, exhibits diverse biological roles including the antitumor activity. In this study, we evaluated the chemosensitive role of astragaloside IV in non-small cell lung cancer cells. Cell Counting Kit-8 analysis was performed to determine cell viability. Real-time polymerase chain reaction and western blot were used to measure the messenger RNA and protein expression. Results showed that astragaloside IV treatment could suppress the proliferation of non-small cell lung cancer cells. In addition, combined treatment with astragaloside IV remarkably enhanced the chemosensitivity to gefitinib in three non-small cell lung cancer cell lines including NCI-H1299, HCC827, and A549. Furthermore, compared with gefitinib-treated cells, the messenger RNA expression of SIRT6 was obviously increased in non-small cell lung cancer cells treated with gefitinib combined with astragaloside IV. In addition, downregulation of SIRT6 was accomplished using small interference RNA technology. As a result, SIRT6 inhibition abolished the sensitization role of astragaloside IV in non-small cell lung cancer cells. Taken together, these data demonstrated that astragaloside IV sensitized tumor cells to gefitinib via regulation of SIRT6, suggesting that astragaloside IV may serve as potential therapeutic approach for lung cancer.

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Section: Discussionmentioning

confidence: 99%

Astragaloside IV sensitizes non–small cell lung cancer cells to gefitinib potentially via regulation of SIRT6

et al. 2017

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“…These enzymes, collectively referred to as sirtuins, have varied intracellular localization, being nuclear, cytoplasmic, or mitochondrial. Because they represent a direct molecular link between NAD + -dependent metabolism and deacetylase activity, the finding that both SIRT1 and SIRT6 contribute to circadian control has provided the first molecular link between metabolism, aging, and the circadian clock (31,32).…”

Section: Circadian Rhythms In the Chromatin Fibermentioning

confidence: 99%

Chromatin landscape and circadian dynamics: Spatial and temporal organization of clock transcription

Aguilar-Arnal

Sassone–Corsi

2014

Proc. Natl. Acad. Sci. U.S.A.

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Circadian rhythms drive the temporal organization of a wide variety of physiological and behavioral functions in ∼24-h cycles. This control is achieved through a complex program of gene expression. In mammals, the molecular clock machinery consists of interconnected transcriptional-translational feedback loops that ultimately ensure the proper oscillation of thousands of genes in a tissue-specific manner. To achieve circadian transcriptional control, chromatin remodelers serve the clock machinery by providing appropriate oscillations to the epigenome. Recent findings have revealed the presence of circadian interactomes, nuclear "hubs" of genome topology where coordinately expressed circadian genes physically interact in a spatial and temporal-specific manner. Thus, a circadian nuclear landscape seems to exist, whose interplay with metabolic pathways and clock regulators translates into specific transcriptional programs. Deciphering the molecular mechanisms that connect the circadian clock machinery with the nuclear landscape will reveal yet unexplored pathways that link cellular metabolism to epigenetic control.circadian rhythms | chromatin | epigenetics | nuclear organization

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“…20,21 In contrast, SIRT6 appears to be downregulated in other types of solid tumors (ie, gastrointestinal cancers, including colorectal and pancreatic cancer), which results in increased glycolysis, glucose uptake, and MYC activity. 18,22 To date, the role of SIRT6 in hematologic malignancies, including MM, is unknown. In this study, we have characterized the biological role, prognostic significance, and potential clinical relevance of SIRT6 expression in MM.…”

Section: Sirtuins (Sirts) Are Nadmentioning

confidence: 99%

Evidence for a role of the histone deacetylase SIRT6 in DNA damage response of multiple myeloma cells

Cea

Cagnetta

Adamia

et al. 2016

Blood

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Key Points• SIRT6 is highly expressed in multiple myeloma cells and blocks expression of ERKregulated genes.• Targeting SIRT6 enzymatic activity sensitizes multiple myeloma cells to DNAdamaging agents.Multiple myeloma (MM) is characterized by a highly unstable genome, with aneuploidy observed in nearly all patients. The mechanism causing this karyotypic instability is largely unknown, but recent observations have correlated these abnormalities with dysfunctional DNA damage response. Here, we show that the NAD 1 -dependent deacetylase SIRT6 is highly expressed in MM cells, as an adaptive response to genomic stability, and that high SIRT6 levels are associated with adverse prognosis. Mechanistically, SIRT6 interacts with the transcription factor ELK1 and with the ERK signaling-related gene. By binding to their promoters and deacetylating H3K9 at these sites, SIRT6 downregulates the expression of mitogen-activated protein kinase (MAPK) pathway genes, MAPK signaling, and proliferation. In addition, inactivation of ERK2/p90RSK signaling triggered by high SIRT6 levels increases DNA repair via Chk1 and confers resistance to DNA damage. Using genetic and biochemical studies in vitro and in human MM xenograft models, we show that SIRT6 depletion both enhances proliferation and confers sensitization to DNA-damaging agents. Our findings therefore provide insights into the functional interplay between SIRT6 and DNA repair mechanisms, with implications for both tumorigenesis and the treatment of MM. (Blood. 2016;127(9):1138-1150 IntroductionGenomic instability is a common feature of monoclonal gammopathies, resulting in complex genetic changes associated with disease progression from monoclonal gammopathy of undetermined significance to active multiple myeloma (MM) to plasma cell leukemia.1,2 Although alterations in DNA damage checkpoint proteins are less common (10% to 15%) in blood cancers compared with solid tumors, [3][4][5] MM cells do manifest a dysfunctional DNA-damage response (DDR), a key determinant of their genomic instability. [6][7][8] Identifying proteins and signaling pathways that protect MM cells from cumulative genomic instability may therefore lead to innovative therapeutic opportunities, as exemplified by the clinical efficacy of PARP inhibitors in the context of breast and ovarian tumors lacking functional BRCA1 or BRCA2. 9,10 In MM cells, direct evidence of homozygous loss or mutations in BRCA1/2 or other DDR genes is lacking, but increased DNA repair activity has been reported. 11,12 Thus, identification of adaptive pathways for coping with genomic instability in MM may similarly provide the framework for new therapeutic strategies. Sirtuins (SIRTs) are NAD1 -degrading enzymes involved in a variety of biological processes, ranging from metabolism to lifespan regulation. 13,14 Of the 7 sirtuin family members, only SIRT6 clearly contributes to DNA repair. [15][16][17][18] Consistently, murine SIRT6 knockout cells exhibit genomic instability and hypersensitivity to DNA-damaging agents. 15,17,19 Moreover...

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Partitioning Circadian Transcription by SIRT6 Leads to Segregated Control of Cellular Metabolism

Cited by 256 publications

References 61 publications

Astragaloside IV sensitizes non–small cell lung cancer cells to gefitinib potentially via regulation of SIRT6

Astragaloside IV sensitizes non–small cell lung cancer cells to gefitinib potentially via regulation of SIRT6

Chromatin landscape and circadian dynamics: Spatial and temporal organization of clock transcription

Evidence for a role of the histone deacetylase SIRT6 in DNA damage response of multiple myeloma cells

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