SIRT2, a tubulin deacetylase, acts to block the entry to chromosome condensation in response to mitotic stress

Inoue, Toshiaki; Hiratsuka, Masanori; Osaki, Mitsuhiko; Yamada, Hiroshi; Kishimoto, Itsuko; Yamaguchi, Shigeyuki; Nakano, Shin-ichi; Katoh, Motonobu; Ito, Hisao; Oshimura, Mitsuo

doi:10.1038/sj.onc.1209857

Cited by 216 publications

(200 citation statements)

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“…An early study suggests that downregulation of SIRT2 confers glioma cell resistance to microtubule inhibitors, such as nocodazole. 35 However, a recent study demonstrates that knocking down SIRT2 expression results in caspase 3-dependent apoptosis in glioma cells. 36 Furthermore, a number of other recent papers demonstrate that SIRT2 is an oncogenic factor and a novel target for cancer therapy.…”

Section: Discussionmentioning

confidence: 99%

The histone deacetylase SIRT2 stabilizes Myc oncoproteins

et al. 2012

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Myc oncoproteins are commonly upregulated in human cancers of different organ origins, stabilized by Aurora A, degraded through ubiquitin-proteasome pathway-mediated proteolysis, and exert oncogenic effects by modulating gene and protein expression. Histone deacetylases are emerging as targets for cancer therapy. Here we demonstrated that the class III histone deacetylase SIRT2 was upregulated by N-Myc in neuroblastoma cells and by c-Myc in pancreatic cancer cells, and that SIRT2 enhanced N-Myc and c-Myc protein stability and promoted cancer cell proliferation. Affymetrix gene array studies revealed that the gene most significantly repressed by SIRT2 was the ubiquitin-protein ligase NEDD4. Consistent with this finding, SIRT2 repressed NEDD4 gene expression by directly binding to the NEDD4 gene core promoter and deacetylating histone H4 lysine 16. Importantly, NEDD4 directly bound to Myc oncoproteins and targeted Myc oncoproteins for ubiquitination and degradation, and small-molecule SIRT2 inhibitors reactivated NEDD4 gene expression, reduced N-Myc and c-Myc protein expression, and suppressed neuroblastoma and pancreatic cancer cell proliferation. Additionally, SIRT2 upregulated and small-molecule SIRT2 inhibitors decreased Aurora A expression. Our data reveal a novel pathway critical for Myc oncoprotein stability, and provide important evidences for potential application of SIRT2 inhibitors for the prevention and therapy of Myc-induced malignancies. The Myc family of oncoproteins are commonly upregulated in human cancer. MYCN oncogene amplification and consequent N-Myc oncoprotein overexpression occur in 20-25% of neuroblastoma and correlate with a poor patient outcome. 1-3 MYC oncogene amplification occurs in 54% of human pancreatic cancer cell lines 4 and 33% of human primary pancreatic tumors, 5 and significant c-Myc oncoprotein overexpression is seen in B50% of human primary pancreatic tumors. 6 Stabilization and degradation of Myc oncoproteins are controlled by ordered phosphorylation at serine 62 (S62) and threonine 58 (T58) and consequent ubiquitinproteasome pathway-mediated proteolysis. 7-9 Aurora A interacts with both N-Myc and ubiquitin, and blocks ubiquitin-regulated N-Myc protein degradation. 8 Myc oncoproteins induce malignant transformation by binding to cognate DNA sequences and consequently modulating gene transcription 10-13 as well as by enhancing ribosome biogenesis and consequently upregulating protein expression, 14,15 leading to cell proliferation.Recruitment of histone deacetylase (HDACs) to gene promoters induces histone hypoacetylation and transcriptional repression, particularly of tumor suppressor genes. 16 In a comprehensive panel of normal cells, cancer cell lines, normal tissues, and primary tumors, global loss of monoacetylation of histone H4 at lysine 16 (H4K16) is seen only in cancer cells and is associated with early stages of tumorigenesis. 17 One of the HDACs that cause H4K16 deacetylation is the class III HDAC SIRT2, which shows a strong preference for acetylated H4K16. 18 Mo...

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Section: Discussionmentioning

confidence: 99%

The histone deacetylase SIRT2 stabilizes Myc oncoproteins

et al. 2012

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“…During mitosis, phosphorylation stabilizes SIRT2, which shuttles to the nucleus and colocalizes with chromatin (Dryden et al, 2003;Inoue et al, 2006). In the nucleus, SIRT2 deacetylates H4-K16, and during the G2/M transition, global levels of H4-K16 acetylation decrease, which may aid in chromatin condensation (Vaquero et al, 2006).…”

Section: Regulation Of a Mitotic Checkpoint By Sirt2mentioning

confidence: 99%

“…In the nucleus, SIRT2 deacetylates H4-K16, and during the G2/M transition, global levels of H4-K16 acetylation decrease, which may aid in chromatin condensation (Vaquero et al, 2006). As overexpression of SIRT2 delays mitotic exit, SIRT2 might function as a mitotic checkpoint protein by preventing chromatin condensation in response to mitotic stress (Dryden et al, 2003;Inoue et al, 2006). A loss of SIRT2 expression is seen in gliomas, which might compromise the mitotic checkpoint, contributing to genomic instability and tumorigenesis (Dryden et al, 2003;Hiratsuka et al, 2003;Inoue et al, 2006).…”

Section: Regulation Of a Mitotic Checkpoint By Sirt2mentioning

confidence: 99%

“…As overexpression of SIRT2 delays mitotic exit, SIRT2 might function as a mitotic checkpoint protein by preventing chromatin condensation in response to mitotic stress (Dryden et al, 2003;Inoue et al, 2006). A loss of SIRT2 expression is seen in gliomas, which might compromise the mitotic checkpoint, contributing to genomic instability and tumorigenesis (Dryden et al, 2003;Hiratsuka et al, 2003;Inoue et al, 2006). The proposed role of SIRT2 in regulating a mitotic checkpoint through global deacetylation of H4K-16 suggests that SIRT2 could guard against cells undergoing division when DNA damage is present.…”

Section: Regulation Of a Mitotic Checkpoint By Sirt2mentioning

confidence: 99%

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Sirtuins: critical regulators at the crossroads between cancer and aging

2007

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Sirtuins (SIRTs 1À7), or class III histone deacetylases (HDACs), are protein deacetylases/ADP ribosyltransferases that target a wide range of cellular proteins in the nucleus, cytoplasm, and mitochondria for post-translational modification by acetylation (SIRT1, -2, -3 and -5) or ADP ribosylation (SIRT4 and -6). The orthologs of sirtuins in lower organisms play a critical role in regulating lifespan. As cancer is a disease of aging, we discuss the growing implications of the sirtuins in protecting against cancer development. Sirtuins regulate the cellular responses to stress and ensure that damaged DNA is not propagated and that mutations do not accumulate. SIRT1 also promotes replicative senescence under conditions of chronic stress. By participating in the stress response to genomic insults, sirtuins are thought to protect against cancer, but they are also emerging as direct participants in the growth of some cancers. Here, we review the growing implications of sirtuins both in cancer prevention and as specific and novel cancer therapeutic targets.

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“…SIRT2 is a histone deacetylase with a preference for histone H4 as a substrate [Vaquero et al, 2006], and has been shown to regulate mitotic exit [Dryden et al, 2003] and chromosomal condensation during mitosis [Vaquero et al, 2006;Inoue et al, 2007]. However, unlike the nuclear SIRT1, SIRT2 is more predominantly a cytoplasmic protein that colocalizes with microtubules [North et al, 2003].…”

Section: Introductionmentioning

confidence: 99%

SIRT2, tubulin deacetylation, and oligodendroglia differentiation

Tang

Chua

2007

Cell Motil. Cytoskeleton

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The mammalian silent information regulator 2 (SIRT2) is an NAD-dependent histone deacetylase with known roles in the regulation of the cell cycle. SIRT2 is also a tubulin deacetylase functioning as an early mitotic checkpoint, but its roles in regulating cytoplasmic microtubule dynamics were unknown. Novel findings now indicate that SIRT2 is specifically enriched in brain oligodendroglia, where it functions specifically in modulating the oligodendrocyte cytoskeleton during its differentiation and maturation. Cell Motil.

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SIRT2, a tubulin deacetylase, acts to block the entry to chromosome condensation in response to mitotic stress

Cited by 216 publications

References 42 publications

The histone deacetylase SIRT2 stabilizes Myc oncoproteins

The histone deacetylase SIRT2 stabilizes Myc oncoproteins

Sirtuins: critical regulators at the crossroads between cancer and aging

SIRT2, tubulin deacetylation, and oligodendroglia differentiation

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