title: miR-335 Targets SIAH2 and Confers Sensitivity to Anti-Cancer Drugs by Increasing the Expression of HDAC3.
abstract: We previously reported the role of histone deacetylase 3 (HDAC3) in response to anti-cancer drugs. The decreased expression of HDAC3 in anti-cancer drug-resistant cancer cell line is responsible for the resistance to anti-cancer drugs. In this study, we investigated molecular mechanisms associated with regulation of HDAC3 expression. MG132, an inhibitor of proteasomal degradation, induced the expression of HDAC3 in various anti-cancer drug-resistant cancer cell lines. Ubiquitination of HDAC3 was observed in various anti-cancer drug-resistant cancer cell lines. HDAC3 showed an interaction with SIAH2, an ubiquitin E3 ligase, that has increased expression in various anti-cancer drug-resistant cancer cell lines. miRNA array analysis showed the decreased expression of miR-335 in these cells. Targetscan analysis predicted the binding of miR-335 to the 3'-UTR of SIAH2. miR-335-mediated increased sensitivity to anti-cancer drugs was associated with its effect on HDAC3 and SIAH2 expression. miR-335 exerted apoptotic effects and inhibited ubiquitination of HDAC3 in anti-cancer drug-resistant cancer cell lines. miR-335 negatively regulated the invasion, migration, and growth rate of cancer cells. The mouse xenograft model showed that miR-335 negatively regulated the tumorigenic potential of cancer cells. The down-regulation of SIAH2 conferred sensitivity to anti-cancer drugs. The results of the study indicated that the miR-335/SIAH2/HDAC3 axis regulates the response to anti-cancer drugs.
authors.affiliation: Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chunchon 200-701, Korea.
authors.forename: Youngmi
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chunchon 200-701, Korea.
authors.forename: Hyuna
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chunchon 200-701, Korea.
authors.forename: Deokbum
authors.initials: D
authors.lastname: Park
authors.affiliation: Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chunchon 200-701, Korea.
authors.forename: Dooil
authors.initials: D
authors.lastname: Jeoung
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D064593:Heterografts; D006655:Histone Deacetylases / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000098563:Seven in Absentia Proteins; D000099186:Histone Deacetylase 3
chemical_list: D006655:Histone Deacetylases; D007976:Leupeptins; D035683:MicroRNAs; D009687:Nuclear Proteins; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins; D000099186:Histone Deacetylase 3; C556347:MIRN335 microRNA, human; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde
keywords: SIAH2; anti-cancer drug-resistance; miR-335; ubiquitination