title: The overriding of TRAIL resistance by the histone deacetylase inhibitor MS-275 involves c-myc up-regulation in cutaneous, uveal, and mucosal melanoma.
abstract: Malignant melanoma is a highly aggressive tumor which may occur in the skin, eye, and mucous membranes. The prognosis of melanoma remains poor in spite of therapeutic advances, emphasizing the importance of innovative treatment modalities. Currently, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is showing promising clinical responses, however its use is hampered by intrinsic or acquired melanoma resistance to apoptosis. Recently, we showed that the combination of TRAIL with the class I-specific histone deacetylase inhibitor (HDACi) MS-275 was a privileged way to override TRAIL resistance through down-regulation of cellular Fas-associated death domain (FADD)-like interleukin-1beta-converting enzyme-inhibitory protein (c-FLIP). Here, we elucidated the underlying mechanism and provided evidence that a crucial step in the c-FLIP downregulation triggered by MS-275 implies the up-regulation of c-myc, a transcriptional repressor of c-FLIP. Notably, MS-275 caused H3 histone acetylation at the promoter of c-myc and increased its binding to the c-FLIP promoter, that in turn led to reduced c-FLIP gene transcription. Knockdown of c-myc prevented the MS-275-mediated downregulation of c-FLIP and hindered TRAIL-plus MS-275-induced apoptosis. Findings reported here provide additional knowledge tools for a more aware and effective molecular therapy of melanoma.
authors.affiliation: Department of Experimental Specialized Medical and Surgical and Odontostomatology Sciences, University of Messina, Messina, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Venza
authors.affiliation: Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Visalli
authors.affiliation: Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
authors.forename: Rosaria
authors.initials: R
authors.lastname: Oteri
authors.affiliation: Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Agliano
authors.affiliation: Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Morabito
authors.affiliation: Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy. Electronic address: dteti@unime.it.
authors.forename: Diana
authors.initials: D
authors.lastname: Teti
authors.affiliation: Department of Experimental Specialized Medical and Surgical and Odontostomatology Sciences, University of Messina, Messina, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Venza
mesh_terms: D001549:Benzamides / Q000627:therapeutic use*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D053200:Fas-Associated Death Domain Protein / Q000235:genetics; D055785:Gene Knockdown Techniques; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008545:Melanoma / Q000188:drug therapy*; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis*; D011725:Pyridines / Q000627:therapeutic use*; D012878:Skin Neoplasms / Q000188:drug therapy*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000627:therapeutic use*; D015854:Up-Regulation; D014604:Uveal Neoplasms / Q000188:drug therapy*
chemical_list: D001549:Benzamides; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D016271:Proto-Oncogene Proteins c-myc; D011725:Pyridines; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C118739:entinostat
keywords: Apoptosis; Histone deacetylase inhibitors; MS-275; Melanoma; TRAIL; c-FLIP; c-myc