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

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. Using gene expression analysis, we define a core set of six genes commonly regulated in acute myeloid leukemia (AML) blasts and cell lines. , 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 activation and apoptosis. c-Myc binds to the promoter on the proximal GC box through SP1 or MIZ1, impairing activation. HDACi exposure triggers expression, altering c-Myc- binding. These events do not occur in normal cells. Excitingly, this inverse correlation between TRAIL and c-Myc is supported by HDACi treatment of AML blasts and primary human breast cancer cells. The predictive value of c-Myc to HDACi responsiveness is confirmed in AML patients undergoing HDACi-based clinical trials. Collectively, our findings identify a key role for c-Myc in 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. .