Activation of stress response gene SIRT1 by BCR-ABL promotes leukemogenesis

Yuan, Hongfeng; Wang, Zhiqiang; Li, Ling; Zhang, Hao; Modi, Hardik; Horne, David; Bhatia, Smita; Chen, Wenyong

doi:10.1182/blood-2011-06-361691

Cited by 166 publications

(222 citation statements)

References 50 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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“…This striking result adds a new dimension to previous reports on the antitumor activity of tenovin-6 in melanoma and neuroblastoma xenografts (6,12). Supporting its antitumor activity, tenovin-6 also increases degradation of N-myc and c-myc and it increases the levels of FOXO1 acetylation, which are regulated by SirT1 (12)(13)(14).…”

Section: Introductionsupporting

confidence: 47%

“…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%

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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“…In the past decade, a controversial view of SIRT1 has emerged about its role in tumorigenesis. SIRT1 is found to be overexpressed in many cancers such as prostate, colon, and acute myeloid leukemia (18)(19)(20). Nevertheless, it is reported to function as a tumor promoter and as a tumor suppressor protein.…”

Section: Introductionmentioning

confidence: 99%

Antitumor Effect of SIRT1 Inhibition in Human HCC Tumor Models In Vitro and In Vivo

Portmann

Fahrner

Lechleiter

et al. 2013

Molecular Cancer Therapeutics

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Sirtuins (SIRT1-7) are a highly conserved family of NAD þ -dependent enzymes that control the activity of histone and nonhistone regulatory proteins. SIRT1 is purposed to promote longevity and to suppress the initiation of some cancers. Nevertheless, SIRT1 is reported to function as a tumor suppressor as well as an oncogenic protein. Our data show that compared with normal liver or surrounding tumor tissue, SIRT1 is strongly overexpressed in human hepatocellular carcinoma (HCC). In addition, human HCC cell lines (Hep3B, HepG2, HuH7, HLE, HLF, HepKK1, skHep1) were screened for the expression of the sirtuin family members and only SIRT1 was consistently overexpressed compared with normal hepatocytes. To determine its effect on HCC growth, SIRT1 activity was inhibited either with lentiviruses expressing short hairpin RNAs or with the small molecule inhibitor, cambinol. Knockdown or inhibition of SIRT1 activity had a cytostatic effect, characterized by an altered morphology, impaired proliferation, an increased expression of differentiation markers, and cellular senescence. In an orthotopic xenograft model, knockdown of SIRT1 resulted in 50% fewer animals developing tumors and cambinol treatment resulted in an overall lower tumor burden. Taken together, our data show that inhibition of SIRT1 in HCC cells impairs their proliferation in vitro and tumor formation in vivo. These data suggest that SIRT1 expression positively influences the growth of HCC and support further studies aimed to block its activity alone or in combination as a novel treatment strategy. Mol Cancer Ther; 12(4); 499-508. Ó2013 AACR.

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Activation of stress response gene SIRT1 by BCR-ABL promotes leukemogenesis

Cited by 166 publications

References 50 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

Antitumor Effect of SIRT1 Inhibition in Human HCC Tumor Models In Vitro and In Vivo

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