Activation of tissue transglutaminase transcription by histone deacetylase inhibition as a therapeutic approach for Myc oncogenesis

Liu, Tao; Tee, Andrew E.; Porro, Antônio; Smith, Stewart A.; Dwarte, Tanya; Liu, Pei Yan; Iraci, Nunzio; Sekyere, Eric; Haber, Michelle; Norris, Murray D.; Diolaiti, Daniel; Valle, Giuliano Della; Perini, Giovanni; Marshall, Glenn M.

doi:10.1073/pnas.0705524104

Cited by 97 publications

(124 citation statements)

References 41 publications

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“…6,22,24 Our present study shows that SIRT2 represses NEDD4 gene expression in neuroblastoma and pancreatic cells, that SIRT2 binds to NEDD4 gene core promoter and SIRT2 siRNA increases the presence of acetylated histone H4K16 at NEDD4 gene promoter, and that SIRT2 siRNA enhances NEDD4 promoter activity. These data suggest that SIRT2 represses NEDD4 gene transcription by direct binding to NEDD4 gene core promoter region, deacetylating histone H4K16 and, repressing NEDD4 gene promoter activity.…”

Section: Discussionmentioning

confidence: 90%

“…As SIRT2 is known to block programmed cell death by deacetylating p53 protein, 30 we hypothesize that repression of SIRT2 does not induce significant cell death in BE(2)-C and MiaPaca-2 cells because p53 is mutated in the two cell lines. 6,24 One surprising finding of this study is that knocking down SIRT2 gene expression with siRNAs considerably reduces N-Myc protein expression in neuroblastoma cells and c-Myc protein expression in pancreatic cancer cells, but shows no effect on N-Myc and c-Myc mRNA expression. Consistently, the SIRT2 inhibitor AC-93253 and Salermide decrease the expression of N-Myc and c-Myc protein, but not mRNA.…”

Section: Discussionmentioning

confidence: 95%

“…Importantly, cotransfection with SIRT2 siRNA blocked NEDD4 siRNAmediated N-Myc and c-Myc protein upregulation (Figure 5a). We next cotransfected SHEP neuroblastoma cells, which do not express N-Myc or c-Myc oncoprotein, with an empty vector, N-Myc-overexpressing construct, 24 and/or NEDD4-overexpressing construct. 27 Immunoblot analysis revealed that transfection with the NEDD4 expression construct reduced N-Myc protein expression (Figure 5b).…”

Section: Resultsmentioning

confidence: 99%

“…6,22,24 We therefore performed chromatin immunoprecipitation (ChIP) assays with an anti-SIRT2 antibody (Ab), an anti-acetylated histone H4 lysine 16 (acetyl H4K16) Ab or a control Ab and PCR with primers targeting upstream control region or core promoter region of the NEDD4 gene promoter. The ChIP assays showed that the anti-SIRT2 and the anti-acetyl H4K16 antibodies efficiently immunoprecipitated the region of NEDD4 gene core promoter (Figure 4d).…”

Section: Resultsmentioning

confidence: 99%

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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: 90%

Section: Discussionmentioning

confidence: 95%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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The histone deacetylase SIRT2 stabilizes Myc oncoproteins

et al. 2012

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“…HDACs also facilitate MYC's oncogenic function as a transcription factor, as they are often recruited to the promoter regions of some MYC-targeted genes to facilitate MYC-mediated regulation of transcription. HDAC inhibitors thus decrease MYC gene expression and restore the expression of genes coordinately suppressed by MYC family members and HDACs in multiple cancer cell types, including DLBCL and NMC (19)(20)(21)(22)(23)(24)(25).…”

Section: Introductionmentioning

confidence: 99%

Dual HDAC and PI3K Inhibitor CUDC-907 Downregulates MYC and Suppresses Growth of MYC-dependent Cancers

Sun

Atoyan

Borek

et al. 2017

Molecular Cancer Therapeutics

116

104

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Upregulation of MYC is a common driver event in human cancers, and some tumors depend on MYC to maintain transcriptional programs that promote cell growth and proliferation. Preclinical studies have suggested that individually targeting upstream regulators of MYC, such as histone deacetylases (HDAC) and phosphoinositide 3-kinases (PI3K), can reduce MYC protein levels and suppress the growth of MYCdriven cancers. Synergy between HDAC and PI3K inhibition in inducing cancer cell death has also been reported, but the involvement of MYC regulation is unclear. In this study, we demonstrated that HDAC and PI3K inhibition synergistically downregulates MYC protein levels and induces apoptosis in "double-hit" (DH) diffuse large B-cell lymphoma (DLBCL) cells. Furthermore, CUDC-907, a small-molecule dual-acting inhibitor of both class I and II HDACs and class I PI3Ks, effectively suppresses the growth and survival of MYC-altered or MYC-dependent cancer cells, such as DH DLBCL and BRD-NUT fusion-positive NUT midline carcinoma (NMC) cells, and MYC protein downregulation is an early event induced by CUDC-907 treatment. Consistently, the antitumor activity of CUDC-907 against multiple MYC-driven cancer types was also demonstrated in animal models, including DLBCL and NMC xenograft models, Myc transgenic tumor syngeneic models, and MYC-amplified solid tumor patient-derived xenograft (PDX) models. Our findings suggest that dual function HDAC and PI3K inhibitor CUDC-907 is an effective agent targeting MYC and thus may be developed as potential therapy for MYCdependent cancers.

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Physiopathological Roles of Human Transglutaminase 2

Gentile

2011

Advances in Enzymology - And Related Areas of Molecular Biology

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Activation of tissue transglutaminase transcription by histone deacetylase inhibition as a therapeutic approach for Myc oncogenesis

Cited by 97 publications

References 41 publications

The histone deacetylase SIRT2 stabilizes Myc oncoproteins

The histone deacetylase SIRT2 stabilizes Myc oncoproteins

Dual HDAC and PI3K Inhibitor CUDC-907 Downregulates MYC and Suppresses Growth of MYC-dependent Cancers

Physiopathological Roles of Human Transglutaminase 2

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