1. c-Myc modulation & acetylation is a key HDAC inhibitor target in cancer
- Author
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Ciro Abbondanza, Mariarosaria Conte, Angela Nebbioso, Vincenzo Carafa, Lucia Altucci, Gabriella Lania, Valeria Belsito Petrizzi, Francesco Iovino, Francesco Paolo Tambaro, Hendrik G. Stunnenberg, Concetta Ingenito, Isabella Pallavicini, Rosaria Benedetti, Matthias Nees, Guillermo Garcia-Manero, Joost H.A. Martens, Saverio Minucci, Nebbioso, Angela, Carafa, Vincenzo, Conte, Mariarosaria, Tambaro, Francesco Paolo, Abbondanza, Ciro, Martens, Joost H. A, Nees, Matthia, Benedetti, Rosaria, Pallavicini, Isabella, Minucci, Saverio, Garcia Manero, G, Iovino, Francesco, Lania, Gabriella, Ingenito, Concetta, Belsito Petrizzi, Valeria, Stunnenberg, Hendrik G, and Altucci, Lucia
- Subjects
0301 basic medicine ,Cancer Research ,Sp1 Transcription Factor ,Kruppel-Like Transcription Factors ,Histone Deacetylase 1 ,Proto-Oncogene Proteins c-myc ,TNF-Related Apoptosis-Inducing Ligand ,03 medical and health sciences ,Cell Line, Tumor ,Neoplasms ,hemic and lymphatic diseases ,medicine ,Humans ,Molecular Biology ,Regulation of gene expression ,Clinical Trials as Topic ,Gene Expression Regulation, Leukemic ,business.industry ,Myeloid leukemia ,Cancer ,Acetylation ,medicine.disease ,c-Myc modulation ,3. Good health ,Histone Deacetylase Inhibitors ,Leukemia ,030104 developmental biology ,Oncology ,Apoptosis ,Immunology ,Cancer cell ,Cancer research ,Histone deacetylase ,business ,Ex vivo ,Protein Binding ,Signal Transduction - Abstract
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/Results: Using gene expression analysis, we define a core set of 6 genes commonly regulated in acute myeloid leukemia (AML) blasts and cell lines. c-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. 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.
- Published
- 2017