The c-MYC oncoprotein, the NAMPT enzyme, the SIRT1-inhibitor DBC1, and the SIRT1 deacetylase form a positive feedback loop

Menssen, Antje; Hydbring, Per; Kapelle, Karsten; Vervoorts, Jörg; Diebold, Joachim; Lüscher, Bernhard; Larsson, Lars‐Gunnar; Hermeking, Heiko

doi:10.1073/pnas.1105304109

Cited by 246 publications

(279 citation statements)

References 89 publications

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“…In terms of the regulation of estrogen receptor α (ERα) activity, DBC1 and SIRT1 reciprocally interacted with the cell cycle and apoptosis regulator 1 (CCAR1), and modulate its co-activator function to ERα (20). Furthermore, the inactivation of SIRT1 or the introduction of DBC1 promoted c-MYC-induced apoptosis in different cell lines (21). In the present study, we found DBC1 is associated with SIRT1, but that it does not function as a negative regulator of SIRT1 in HCC.…”

Section: Discussionmentioning

confidence: 49%

DBC1 does not function as a negative regulator of SIRT1 in liver cancer

et al. 2012

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Abstract. The putative tumor suppressor, DBC1 (deleted in breast cancer-1), was recently found to negatively regulate SIRT1 in vitro and in vivo, but the mechanism whereby DBC1 regulates SIRT1 in liver cancer remains to be elucidated. In this study, it was found that although the expression of DBC1 and SIRT1 was not aberrantly regulated in a large cohort of human hepatocellular carcinoma (HCC) patients, these proteins were highly overexpressed in a subset of HCC tissues compared with surrounding non-cancer tissues. In liver cancer, DBC1 and SIRT1 were found to be positively correlated. Inactivation of DBC1 or SIRT1 reduced SNU-182 (a liver cancer cell line) proliferation as determined by MTT viability assays. Notably, although DBC1 functions as a negative regulator of SIRT1 in A549 lung cancer cells since it suppresses the deacetylase activity of the p53 protein, it did not affect the p53 deacetylase activity of SIRT1 in SNU-182 cells. Taken together, we conclude that DBC1 is associated with SIRT1 in HCC, but that it does not inhibit SIRT1.

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Section: Discussionmentioning

confidence: 49%

DBC1 does not function as a negative regulator of SIRT1 in liver cancer

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: Introductionmentioning

confidence: 47%

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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“…Moreover, SIRT1 is known to directly regulate c-Myc transcriptional activity in cancer cells, either via the deacetylation of c-Myc or by binding c-Myc and promoting its association with Max. [110][111][112][113] In this regard, it is intriguing that David Sinclair's group now reveals for the first time that the nuclear ability of SIRT1/HIF-1α to inhibit mitochondrial OXPHOS genes functions by decreasing c-Myc-regulated transcription of the key mitochondrial transcription factor A (TFAM). 23 TFAM is required for mitochondrial DNA replication, transcription, and maintenance, and low levels of TFAM appear to lead to first-phase OXPHOS dysfunction triggered by the aging-associated decline of NAD + .…”

Section: Gerometabolites and Oncometabolites Share A Communication LImentioning

confidence: 99%