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

Abstract

<b>Purpose:</b> 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.<b>Experimental Design and Results:</b> Using gene expression analysis, we define a core set of six genes commonly regulated in acute myeloid leukemia (AML) blasts and cell lines. <i>MYC</i>, 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 <i>TRAIL</i> activation and apoptosis. c-Myc binds to the <i>TRAIL</i> promoter on the proximal GC box through SP1 or MIZ1, impairing <i>TRAIL</i> activation. HDACi exposure triggers <i>TRAIL</i> expression, altering c-Myc-<i>TRAIL</i> binding. These events do not occur in normal cells. Excitingly, this inverse correlation between TRAIL and c-Myc is supported by HDACi treatment <i>ex vivo</i> of AML blasts and primary human breast cancer cells. The predictive value of c-Myc to HDACi responsiveness is confirmed <i>in vivo</i> in AML patients undergoing HDACi-based clinical trials.<b>Conclusions:</b> Collectively, our findings identify a key role for c-Myc in <i>TRAIL</i> 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. <i>Clin Cancer Res; 23(10); 2542-55. ©2016 AACR</i>.