title: Therapeutic Targeting of miR-29b/HDAC4 Epigenetic Loop in Multiple Myeloma.
abstract: Epigenetic abnormalities are common in hematologic malignancies, including multiple myeloma, and their effects can be efficiently counteracted by a class of tumor suppressor miRNAs, named epi-miRNAs. Given the oncogenic role of histone deacetylases (HDAC) in multiple myeloma, we investigated whether their activity could be antagonized by miR-29b, a well-established epi-miRNA. We demonstrated here that miR-29b specifically targets HDAC4 and highlighted that both molecules are involved in a functional loop. In fact, silencing of HDAC4 by shRNAs inhibited multiple myeloma cell survival and migration and triggered apoptosis and autophagy, along with the induction of miR-29b expression by promoter hyperacetylation, leading to the downregulation of prosurvival miR-29b targets (SP1, MCL-1). Moreover, treatment with the pan-HDAC inhibitor SAHA upregulated miR-29b, overcoming the negative control exerted by HDAC4. Importantly, overexpression or inhibition of miR-29b, respectively, potentiated or antagonized SAHA activity on multiple myeloma cells, as also shown in vivo by a strong synergism between miR-29b synthetic mimics and SAHA in a murine xenograft model of human multiple myeloma. Altogether, our results shed light on a novel epigenetic circuitry regulating multiple myeloma cell growth and survival and open new avenues for miR-29b-based epi-therapeutic approaches in the treatment of this malignancy. Mol Cancer Ther; 15(6); 1364-75. ©2016 AACR.
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University and Translational Medical Oncology Unit, Salvatore Venuta University Campus, Catanzaro, Italy. tassone@unicz.it amodio@unicz.it.
authors.forename: Nicola
authors.initials: N
authors.lastname: Amodio
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University and Translational Medical Oncology Unit, Salvatore Venuta University Campus, Catanzaro, Italy.
authors.forename: Maria Angelica
authors.initials: MA
authors.lastname: Stamato
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University and Translational Medical Oncology Unit, Salvatore Venuta University Campus, Catanzaro, Italy.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Gullà
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University and Translational Medical Oncology Unit, Salvatore Venuta University Campus, Catanzaro, Italy.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Morelli
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University and Translational Medical Oncology Unit, Salvatore Venuta University Campus, Catanzaro, Italy.
authors.forename: Enrica
authors.initials: E
authors.lastname: Romeo
authors.affiliation: Laboratory of Tissue Engineering - Innovative Technology Platforms for Tissue Engineering (PON01-00829), Rizzoli Orthopedic Institute, Palermo, Italy.
authors.forename: Lavinia
authors.initials: L
authors.lastname: Raimondi
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University and Translational Medical Oncology Unit, Salvatore Venuta University Campus, Catanzaro, Italy.
authors.forename: Maria Rita
authors.initials: MR
authors.lastname: Pitari
authors.affiliation: Department of Biology, University "Federico II" of Naples, Naples, Italy.
authors.forename: Ida
authors.initials: I
authors.lastname: Ferrandino
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Misso
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Caraglia
authors.affiliation: Department of Biology, Ecology and Earth Sciences (Di.B.E.S.T.), Transmission Electron Microscopy Laboratory, Centre for Microscopy and Microanalysis (CM2), University of Calabria, Rende, Italy.
authors.forename: Ida
authors.initials: I
authors.lastname: Perrotta
authors.affiliation: Department of Medical Sciences, University of Milan, Hematology 1, IRCCS Policlinico Foundation, Milan, Italy.
authors.forename: Antonino
authors.initials: A
authors.lastname: Neri
authors.affiliation: Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Fulciniti
authors.affiliation: Oncology Department, Antwerp University Hospital (UZA) and Center for Oncological Research (CORE) Antwerp University, Antwerp, Belgium.
authors.forename: Christian
authors.initials: C
authors.lastname: Rolfo
authors.affiliation: Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
authors.affiliation: Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. VA Boston Healthcare System, West Roxbury, Boston, Massachusetts.
authors.forename: Nikhil C
authors.initials: NC
authors.lastname: Munshi
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University and Translational Medical Oncology Unit, Salvatore Venuta University Campus, Catanzaro, Italy.
authors.forename: Pierosandro
authors.initials: P
authors.lastname: Tagliaferri
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University and Translational Medical Oncology Unit, Salvatore Venuta University Campus, Catanzaro, Italy. Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania. tassone@unicz.it amodio@unicz.it.
authors.forename: Pierfrancesco
authors.initials: P
authors.lastname: Tassone
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D044127:Epigenesis, Genetic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005822:Genetic Vectors / Q000008:administration & dosage; D006655:Histone Deacetylases / Q000235:genetics*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage* / Q000494:pharmacology; D051379:Mice; D035683:MicroRNAs / Q000008:administration & dosage / Q000235:genetics*; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D009368:Neoplasm Transplantation; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000494:pharmacology*; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D000077337:Vorinostat
chemical_list: D006877:Hydroxamic Acids; C532045:MIRN29a microRNA, human; D035683:MicroRNAs; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D000077337:Vorinostat; C400300:HDAC4 protein, human; D006655:Histone Deacetylases