C-Myc modulation and acetylation is a key HDAC inhibitor target in cancer

Angela Nebbioso, Vincenzo Carafa, Mariarosaria Conte, Francesco Paolo Tambaro, Abbondanza Ciro, Joost Martens, Matthias Nees, Rosaria Benedetti, Isabella Pallavicini, Saverio Minucci, Guillermo Garcia-Manero, Francesco Iovino, Gabriella Lania, Concetta Ingenito, Valeria Belsito Petrizzi, Hendrik G. Stunnenberg, Lucia Altucci

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

100 Citaten (Scopus)

Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)2542-2555
Aantal pagina's14
TijdschriftClinical Cancer Research
Volume23
Nummer van het tijdschrift10
DOI's
StatusGepubliceerd - 2017
Extern gepubliceerdJa

Vingerafdruk

Duik in de onderzoeksthema's van 'C-Myc modulation and acetylation is a key HDAC inhibitor target in cancer'. Samen vormen ze een unieke vingerafdruk.

Citeer dit