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Publication year
2017Source
Clinical Cancer Research, 23, 10, (2017), pp. 2542-2555ISSN
Publication type
Article / Letter to editor

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Organization
Molecular Biology
Journal title
Clinical Cancer Research
Volume
vol. 23
Issue
iss. 10
Page start
p. 2542
Page end
p. 2555
Subject
Molecular BiologyAbstract
PURPOSE: Histone deacetylase inhibitors (HDACi) are promising anticancer drugs. Although some HDACi have entered the clinic, the mechanism(s) underlying their tumor selectivity are poorly understood. Experimental Design/Results: Using gene expression analysis, we define a core set of 6 genes commonly regulated in acute myeloid leukemia (AML) blasts and cell lines. c-Myc, the most prominently modulated, is preferentially altered in leukemia. Upon HDACi treatment, c-Myc is acetylated at lysine 323 and its expression decreases, leading to TRAIL activation and apoptosis. c-Myc binds to the TRAIL promoter on the proximal GC box through Sp1 or Miz1, impairing TRAIL activation. HDACi exposure triggers TRAIL expression, altering c-Myc-TRAIL binding. These events do not occur in normal cells. Excitingly, this inverse correlation between TRAIL and c-Myc is supported by HDACi treatment ex vivo of AML blasts and primary human breast cancer cells. The predictive value of c-Myc to HDACi responsiveness is confirmed in vivo in AML patients undergoing HDACi-based clinical trials. CONCLUSIONS: Collectively, our findings identify a key role for c-Myc in TRAIL deregulation and as a biomarker of the anticancer action of HDACi in AML. The potential improved patient stratification could pave the way towards personalized therapies.
This item appears in the following Collection(s)
- Academic publications [227900]
- Electronic publications [107393]
- Faculty of Science [33781]
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