title: Transcript, methylation and molecular docking analyses of the effects of HDAC inhibitors, SAHA and Dacinostat, on SMN2 expression in fibroblasts of SMA patients.
abstract: Several histone deacetylase inhibitors (HDACis) are known to increase Survival Motor Neuron 2 (SMN2) expression for the therapy of spinal muscular atrophy (SMA). We aimed to compare the effects of suberoylanilide hydroxamic acid (SAHA) and Dacinostat, a novel HDACi, on SMN2 expression and to elucidate their acetylation effects on the methylation of the SMN2. Cell-based assays using type I and type II SMA fibroblasts examined changes in transcript expressions, methylation levels and protein expressions. In silico methods analyzed the intermolecular interactions between each compound and HDAC2/HDAC7. SMN2 mRNA transcript levels and SMN protein levels showed notable increases in both cell types, except for Dacinostat exposure on type II cells. However, combined compound exposures showed less pronounced increase in SMN2 transcript and SMN protein level. Acetylation effects of SAHA and Dacinostat promoted demethylation of the SMN2 promoter. The in silico analyses revealed identical binding sites for both compounds in HDACs, which could explain the limited effects of the combined exposure. With the exception on the effect of Dacinostat in Type II cells, we have shown that SAHA and Dacinostat increased SMN2 transcript and protein levels and promoted demethylation of the SMN2 gene.
authors.affiliation: Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kerian Kelantan, Malaysia.
authors.forename: Jafar
authors.initials: J
authors.lastname: Mohseni
authors.affiliation: Pharmaceutical Design and Simulation Laboratory, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Pulau Pinang, Malaysia.|Faculty of Pharmacy & Medical Sciences, Al-Ahliyya Amman University, Amman, Jordan.
authors.forename: Belal O
authors.initials: BO
authors.lastname: Al-Najjar
authors.affiliation: Pharmaceutical Design and Simulation Laboratory, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Pulau Pinang, Malaysia.
authors.forename: Habibah A
authors.initials: HA
authors.lastname: Wahab
authors.affiliation: Department of Pediatrics, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kerian Kelantan, Malaysia.|Center for Neuroscience Services and Research, Universiti Sains Malaysia, Health Campus, Kerian Kelantan, Malaysia.
authors.forename: Z A M H
authors.initials: ZA
authors.lastname: Zabidi-Hussin
authors.affiliation: Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kerian Kelantan, Malaysia.|Center for Neuroscience Services and Research, Universiti Sains Malaysia, Health Campus, Kerian Kelantan, Malaysia.
authors.forename: Teguh Haryo
authors.initials: TH
authors.lastname: Sasongko
mesh_terms: D017398:Alternative Splicing; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D019175:DNA Methylation; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry* / Q000494:pharmacology; D007223:Infant; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D055540:Survival of Motor Neuron 2 Protein / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D012333:RNA, Messenger; D055540:Survival of Motor Neuron 2 Protein; D000077337:Vorinostat