title: 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 toTRAILactivation and apoptosis. c-Myc binds to theTRAILpromoter on the proximal GC box through SP1 or MIZ1, impairingTRAILactivation. HDACi exposure triggersTRAILexpression, altering c-Myc-TRAILbinding. These events do not occur in normal cells. Excitingly, this inverse correlation between TRAIL and c-Myc is supported by HDACi treatmentex vivoof AML blasts and primary human breast cancer cells. The predictive value of c-Myc to HDACi responsiveness is confirmedin vivoin AML patients undergoing HDACi-based clinical trials.Conclusions:Collectively, our findings identify a key role for c-Myc inTRAILderegulation 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.
authors.affiliation: Dipartimento di Biochimica, Biofisica e Patologia Generale, Università degli Studi della Campania 'L. Vanvitelli', Naples, Italy. lucia.altucci@unicampania.it angela.nebbioso@unicampania.it.|Department of Molecular Biology, Faculties of Science and Medicine, Radboud University, Nijmegen Center for Molecular Life Sciences, Nijmegen, the Netherlands.
authors.forename: Angela
authors.initials: A
authors.lastname: Nebbioso
authors.affiliation: Dipartimento di Biochimica, Biofisica e Patologia Generale, Università degli Studi della Campania 'L. Vanvitelli', Naples, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Carafa
authors.affiliation: IRCCS SDN, Naples, Italy.
authors.forename: Mariarosaria
authors.initials: M
authors.lastname: Conte
authors.affiliation: Dipartimento di Biochimica, Biofisica e Patologia Generale, Università degli Studi della Campania 'L. Vanvitelli', Naples, Italy.|Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, Texas.
authors.forename: Francesco Paolo
authors.initials: FP
authors.lastname: Tambaro
authors.affiliation: Dipartimento di Biochimica, Biofisica e Patologia Generale, Università degli Studi della Campania 'L. Vanvitelli', Naples, Italy.
authors.forename: Ciro
authors.initials: C
authors.lastname: Abbondanza
authors.affiliation: Dipartimento di Biochimica, Biofisica e Patologia Generale, Università degli Studi della Campania 'L. Vanvitelli', Naples, Italy.|Department of Molecular Biology, Faculties of Science and Medicine, Radboud University, Nijmegen Center for Molecular Life Sciences, Nijmegen, the Netherlands.
authors.forename: Joost
authors.initials: J
authors.lastname: Martens
authors.affiliation: VTT Technical Research Centre of Finland, Espoo, Finland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Nees
authors.affiliation: Dipartimento di Biochimica, Biofisica e Patologia Generale, Università degli Studi della Campania 'L. Vanvitelli', Naples, Italy.
authors.forename: Rosaria
authors.initials: R
authors.lastname: Benedetti
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Pallavicini
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Saverio
authors.initials: S
authors.lastname: Minucci
authors.affiliation: Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, Texas.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Garcia-Manero
authors.affiliation: Dipartimento Scienze Anestesiologiche, Chirurgiche e dell'Emergenza, Università degli Studi della Campania 'L. Vanvitelli', Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Iovino
authors.affiliation: Institute of Genetics and Biophysics (IGB) 'Adriano Buzzati Traverso', Naples, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Lania
authors.affiliation: Division of Onco-Hematology, A. Tortora Hospital, Pagani, Italy.
authors.forename: Concetta
authors.initials: C
authors.lastname: Ingenito
authors.affiliation: Division of Onco-Hematology, A. Tortora Hospital, Pagani, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Belsito Petrizzi
authors.affiliation: Department of Molecular Biology, Faculties of Science and Medicine, Radboud University, Nijmegen Center for Molecular Life Sciences, Nijmegen, the Netherlands.
authors.forename: Hendrik G
authors.initials: HG
authors.lastname: Stunnenberg
authors.affiliation: Dipartimento di Biochimica, Biofisica e Patologia Generale, Università degli Studi della Campania 'L. Vanvitelli', Naples, Italy. lucia.altucci@unicampania.it angela.nebbioso@unicampania.it.|Institute of Genetics and Biophysics (IGB) 'Adriano Buzzati Traverso', Naples, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Altucci
mesh_terms: D000107:Acetylation; D045744:Cell Line, Tumor; D002986:Clinical Trials as Topic; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors / Q000235:genetics*; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D016329:Sp1 Transcription Factor / Q000235:genetics; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics*
chemical_list: D056572:Histone Deacetylase Inhibitors; D051741:Kruppel-Like Transcription Factors; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D016329:Sp1 Transcription Factor; C108209:SP1 protein, human; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C107961:ZBTB17 protein, human; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1