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Clin Cancer Res. 2017 May 15;23(10):2542-2555. doi: 10.1158/1078-0432.CCR-15-2388. Epub 2016 Jun 29.

c-Myc Modulation and Acetylation Is a Key HDAC Inhibitor Target in Cancer.

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Dipartimento di Biochimica, Biofisica e Patologia Generale, Università degli Studi della Campania 'L. Vanvitelli', Naples, Italy.
Department of Molecular Biology, Faculties of Science and Medicine, Radboud University, Nijmegen Center for Molecular Life Sciences, Nijmegen, the Netherlands.
Dipartimento di Biochimica, Biofisica e Patologia Generale, Università degli Studi della Campania 'L. Vanvitelli', Naples, Italy.
IRCCS SDN, Naples, Italy.
Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, Texas.
VTT Technical Research Centre of Finland, Espoo, Finland.
Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
Dipartimento Scienze Anestesiologiche, Chirurgiche e dell'Emergenza, Università degli Studi della Campania 'L. Vanvitelli', Naples, Italy.
Institute of Genetics and Biophysics (IGB) 'Adriano Buzzati Traverso', Naples, Italy.
Division of Onco-Hematology, A. Tortora Hospital, Pagani, Italy.


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 and Results: Using gene expression analysis, we define a core set of six genes commonly regulated in acute myeloid leukemia (AML) blasts and cell lines. 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 toward personalized therapies. Clin Cancer Res; 23(10); 2542-55. ©2016 AACR.

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