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

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.

The lysine acetyltransferase GCN5 contributes to human papillomavirus oncoprotein E7‐induced cell proliferation via up‐regulating E2F1

“…However, the level of c‐Myc binding to E2F1 promoters was not increased when transfected with plasmids encoding c‐Myc (K323Q) that imitated the acetylation status of c‐Myc (data not shown). It was reported that K323 overacetylation might cause reduced c‐Myc protein stability while preserving stability in normal conditions . This observation may explain why c‐Myc was not always highly expressed in E7‐expressing cells .…”

“…Acetylation of c‐Myc by CBP and GCN5/PCAF prevents its degradation and stimulation of c‐Myc transcriptional activity . However, another study found that c‐Myc overacetylation at K323 may reduce its stability . c‐Myc plays a critical role for transformation of human cells by HPV E6 and E7 .…”

“…34,71 However, another study found that c-Myc overacetylation at K323 may reduce its stability. 53 c-Myc plays a critical role for transformation of human cells by HPV E6 and E7. 72,73 c-Myc interacts with and forms a specific complex with high-risk type HPV E7 that augmented c-Myc transactivation activity.…”

“…It was reported that K323 overacetylation might cause reduced c-Myc protein stability while preserving stability in normal conditions. 53 This observation may explain why c-Myc was not always highly expressed in E7-expressing cells. 40 These results indicate that GCN5 could acetylate c-Myc, stabilize it, affect its level of binding to the E2F1 promoter, regulate E2F1 expression and modulate cell cycle progression.…”

Targeting prostate cancer cells with enzalutamide‐HDAC inhibitor hybrid drug 2‐75

“…Both HDAC inhibition and FL AR depletion by 2‐75 could contribute to the observed c‐Myc downregulation. Inhibition/abrogation of c‐Myc is a key event of HDAC inhibition . Various mechanisms, for example, targeting class 1/class 2 (eg, HDAC7) HDACs to suppress MYC transcription or induction of c‐Myc‐targeting microRNA to inhibit protein translation, etc., have been shown to result in persistent down‐modulation of c‐Myc in different cancer phenotypes.…”