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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.

Author information

1
Dipartimento di Biochimica, Biofisica e Patologia Generale, Università degli Studi della Campania 'L. Vanvitelli', Naples, Italy. lucia.altucci@unicampania.it angela.nebbioso@unicampania.it.
2
Department of Molecular Biology, Faculties of Science and Medicine, Radboud University, Nijmegen Center for Molecular Life Sciences, Nijmegen, the Netherlands.
3
Dipartimento di Biochimica, Biofisica e Patologia Generale, Università degli Studi della Campania 'L. Vanvitelli', Naples, Italy.
4
IRCCS SDN, Naples, Italy.
5
Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, Texas.
6
VTT Technical Research Centre of Finland, Espoo, Finland.
7
Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
8
Dipartimento Scienze Anestesiologiche, Chirurgiche e dell'Emergenza, Università degli Studi della Campania 'L. Vanvitelli', Naples, Italy.
9
Institute of Genetics and Biophysics (IGB) 'Adriano Buzzati Traverso', Naples, Italy.
10
Division of Onco-Hematology, A. Tortora Hospital, Pagani, Italy.

Abstract

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.

PMID:
27358484
DOI:
10.1158/1078-0432.CCR-15-2388
[Indexed for MEDLINE]
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