Activation of p53 by SIRT1 Inhibition Enhances Elimination of CML Leukemia Stem Cells in Combination with Imatinib

Li, Ling; Wang, Lisheng; Li, Liang; Wang, Zhiqiang; Ho, YinWei; McDonald, Tinisha; Holyoake, Tessa L.; Chen, Wenyong; Bhatia, Smita

doi:10.1016/j.ccr.2011.12.020

Cited by 370 publications

(397 citation statements)

References 37 publications

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“…19 Additionally, the pan-SIRT inhibitor nicotinamide suppresses growth of carcinogen-induced mouse and human bladder cancer by reducing the deacetylation activity of SIRT2. 40 Consistent with literature, 41,22,[42][43][44][45] our data suggest that repression of SIRT2 alone or simultaneous repression of SIRT1 and SIRT2 with small molecule inhibitors, such as AC-93253, Salermide, Cambinol, and Tenovin-6, could be an effective strategy for the prevention and therapy of Myc-induced neuroblastoma and pancreatic cancer, and possibly other Myc-induced malignancies.…”

Section: Discussionsupporting

confidence: 77%

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: Discussionsupporting

confidence: 77%

The histone deacetylase SIRT2 stabilizes Myc oncoproteins

et al. 2012

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“…Given the promising results obtained with tenovin-6 in imatinib-resistant CML stem cells (11,14), it is of great importance to identify and understand all the effects that the tenovins are inducing in cells. Universities Life Sciences Alliance for PhD funding and N.J. Westwood was a Royal Society University Research Fellow when this work was carried out.…”

Section: Discussionmentioning

confidence: 99%

“…Accordingly, tenovin-6, like other sirtuin inhibitors, increases the levels of K382-acetylated p53 and K40-acetylated a-tubulin in cells (6), 2 well-established substrates for SirT1 and SirT2, respectively (8)(9)(10). Importantly, tenovin-6 eradicates imatinib-resistant chronic myelogenous leukemia (CML) cancer stem cells in vivo (11). This striking result adds a new dimension to previous reports on the antitumor activity of tenovin-6 in melanoma and neuroblastoma xenografts (6,12).…”

Section: Introductionmentioning

confidence: 99%

Tenovin-D3, a Novel Small-Molecule Inhibitor of Sirtuin SirT2, Increases p21 (CDKN1A) Expression in a p53-Independent Manner

McCarthy

Sachweh

Higgins

et al. 2013

Molecular Cancer Therapeutics

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While small-molecule inhibitors of class I/II histone deacetylases (HDAC) have been approved for cancer treatment, inhibitors of the sirtuins (a family of class III HDACs) still require further validation and optimization to enter clinical trials. Recent studies show that tenovin-6, a small-molecule inhibitor of sirtuins SirT1 and SirT2, reduces tumor growth in vivo and eliminates leukemic stem cells in a murine model for chronic myelogenous leukemia. Here, we describe a tenovin analogue, tenovin-D3, that preferentially inhibits sirtuin SirT2 and induces predicted phenotypes for SirT2 inhibition. Unlike tenovin-6 and in agreement with its weak effect on SirT1 (a p53 deacetylase), tenovin-D3 fails to increase p53 levels or transcription factor activity. However, tenovin-D3 promotes expression of the cell-cycle regulator and p53 target p21 WAF1/CIP1 (CDKN1A) in a p53-independent manner. Structure-activity relationship studies strongly support that the ability of tenovin-D3 to inhibit SirT2 contributes to this p53-independent induction of p21. The ability of tenovin-D3 to increase p21 mRNA and protein levels is shared with class I/II HDAC inhibitors currently used in the clinic and therefore suggests that SirT2 inhibition and class I/II HDAC inhibitors have similar effects on cell-cycle progression. Mol Cancer Ther; 12(4); 352-60. Ó2013 AACR.

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“…leukemia cells from patient bone marrow specimens are transplanted into immune-compromised recipient mice, such as NOD-SCID mice [35,36]. Although the model remains technically challenging due to low efficiencies of long-term engraftment and/or biologic variations observed in primary leukemia specimens, development of the novel immunodeficient mouse strain NSG (NOD-SCID IL-2Rc-chaindeficient) has generated an improved model with robust engraftment, providing a better way to analyze human CML stem cells in vivo and test the effectiveness of novel therapies against human CML [37].…”

Section: Mouse Models Of CML and Insights For Cancer Stem Cell Researchmentioning

confidence: 99%

Stem cell maintenance and disease progression in chronic myeloid leukemia

Ito

2013

Int J Hematol

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Chronic myeloid leukemia (CML) is a cancer of blood cells driven by the BCR-ABL1 oncogenic protein tyrosine kinase, which is the product of a reciprocal chromosomal translocation known as the Philadelphia chromosome. Discovery of tyrosine kinase inhibitors targeting the BCR-ABL1 kinase revolutionized CML therapy, but these drugs are unable to eradicate the disease due to the presence of a drug-insensitive stem cell population that sustains continued growth of the malignant cells. Resistance to therapies also increases the risk of relapse and disease progression to a more advanced phase. This review discusses emerging issues in CML research, and describes recent progress in elucidating the mechanisms of CML stem cell maintenance and disease progression.

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Activation of p53 by SIRT1 Inhibition Enhances Elimination of CML Leukemia Stem Cells in Combination with Imatinib

Cited by 370 publications

References 37 publications

The histone deacetylase SIRT2 stabilizes Myc oncoproteins

The histone deacetylase SIRT2 stabilizes Myc oncoproteins

Tenovin-D3, a Novel Small-Molecule Inhibitor of Sirtuin SirT2, Increases p21 (CDKN1A) Expression in a p53-Independent Manner

Stem cell maintenance and disease progression in chronic myeloid leukemia

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