title: Increased Histone Deacetylase Activity Involved in the Suppressed Invasion of Cancer Cells Survived from ALA-Mediated Photodynamic Treatment.
abstract: Previously, we have found that cancer cells survived from 5-Aminolevulinic acid-mediated photodynamic therapy (ALA-PDT) have abnormal mitochondrial function and suppressed cellular invasiveness. Here we report that both the mRNA expression level and enzymatic activity of histone deacetylase (HDAC) were elevated in the PDT-derived variants with dysfunctional mitochondria. The activated HDAC deacetylated histone H3 and further resulted in the reduced migration and invasion, which correlated with the reduced expression of the invasion-related genes, matrix metalloproteinase 9 (MMP9), paternally expressed gene 1 (PEG1), and miR-355, the intronic miRNA. Using chromatin immunoprecipitation, we further demonstrate the reduced amount of acetylated histone H3 on the promoter regions of MMP9 and PEG1, supporting the down-regulation of these two genes in PDT-derived variants. These results indicate that HDAC activation induced by mitochondrial dysfunction could modulate the cellular invasiveness and its related gene expression. This argument was further verified in the 51-10 cybrid cells with the 4977 bp mtDNA deletion and A375 ρ⁰ cells with depleted mitochondria. These results indicate that mitochondrial dysfunction might suppress tumor invasion through modulating histone acetylation.
authors.affiliation: Department of Biochemical Science and Technology, National Taiwan University, Taipei 106, Taiwan. peitzuli@gmail.com.
authors.forename: Pei-Tzu
authors.initials: PT
authors.lastname: Li
authors.affiliation: Department of Biochemical Science and Technology, National Taiwan University, Taipei 106, Taiwan. jane19841114@hotmail.com.
authors.forename: Yi-Jane
authors.initials: YJ
authors.lastname: Tsai
authors.affiliation: Department of Neurology, National Taiwan University Hospital, 7, Chung-Shan South Road, Taipei 100, Taiwan. mjlee@ntu.edu.tw.
authors.forename: Ming-Jen
authors.initials: MJ
authors.lastname: Lee
authors.affiliation: Department of Biochemical Science and Technology, National Taiwan University, Taipei 106, Taiwan. chintin@ntu.edu.tw.
authors.forename: Chin-Tin
authors.initials: CT
authors.lastname: Chen
mesh_terms: D000107:Acetylation; D000622:Aminolevulinic Acid / Q000494:pharmacology*; D001374:Azacitidine / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D047369:Chromatin Immunoprecipitation; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics; D008928:Mitochondria / Q000473:pathology*; D009361:Neoplasm Invasiveness / Q000473:pathology*; D010778:Photochemotherapy / Q000379:methods*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011506:Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; C000608864:MIRN355 microRNA, human; D035683:MicroRNAs; D011506:Proteins; C103637:mesoderm specific transcript protein; C012589:trichostatin A; D000622:Aminolevulinic Acid; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; D006655:Histone Deacetylases; D001374:Azacitidine
keywords: histone acetylation; histone deacetylase; invasion; metalloproteinase 9; mitochondria; paternally expressed gene 1