Journal
MOLECULAR CANCER THERAPEUTICS
Volume 12, Issue 4, Pages 352-360Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-12-0900
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Funding
- Swedish Research Council (Vetenskapsradet)
- Karolinska Institutet
- Swedish Cancer Society
- Cancer Research UK [C8/A6613]
- Association for International Cancer Research (AICR) [10-0043]
- Research and Innovation Services at the University of Dundee
- Agency for Science, Technology and Research, Singapore (A*STAR)
- Center for Advanced Cancer Therapies (ACT) at Karolinska Institutet
- Cancer Research UK
- Scottish Universities Life Sciences Alliance
- Cancer Research UK [6950] Funding Source: researchfish
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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 p21mRNA 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. (C) 2013 AACR.
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