title: Down regulation of miR-202 modulates Mxd1 and Sin3A repressor complexes to induce apoptosis of pancreatic cancer cells.
abstract: Aberrant regulation of microRNA expression in pancreatic cancers has been shown to play an important role in its inherent poor prognosis and malignant potential. MicroRNAs have also been shown to inhibit translation of genes by targeting the 3'-untranslated region (3-UTR) of mRNAs resulting in the inhibition of translation and often destruction of the mRNA. In the present study we investigated the role of the microRNA miR-202 in the apoptotic pathways of pancreatic cancer cells. The adamantyl-related molecule, 3-Cl-AHPC down-regulated expression of miR-202 and miR-578 resulting in the increased expression of mRNA and protein expression of their target genes, Max dimerization protein 1 (Mxd1/Mad1) and the Sin3A associated protein 18 (SAP18). Overexpression of pre-miR-202 led to diminished levels of Mxd1 and blocked the 3-Cl-AHPC-mediated increase in Mxd1 mRNA expression. The addition of the microRNA inhibitor 2'-O-methylated miR-202 enhanced the 3-Cl-AHPC-mediated increase of Mxd1 mRNA levels as well as 3-CI-AHPC-mediated apoptosis. We found increased Mxd1 bound to the Sin3A repressor protein complex through its increased binding with HDAC-2 and subsequently enhanced transcriptional repression in cells as evidenced by increased HDAC activity. Mxd1 also repressed human telomerase reverse transcriptase (hTERT) mRNA expression through its increased binding to the hTERT promoter site and resulted in decreased telomerase activity in cells. Our results demonstrate that down regulation of miR-202 increased the expression of its target Mxd1, followed by Mxd1 recruitment to the Sin3A repressor complex and through its dimerization with Max, and increased repression of Myc-Max target proteins.
authors.affiliation: a John D Dingell VA Medical Center; Department of Oncology ; Detroit , MI USA.
authors.forename: Lulu
authors.initials: L
authors.lastname: Farhana
authors.forename: Marcia I
authors.initials: MI
authors.lastname: Dawson
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Fontana
mesh_terms: D020413:3' Untranslated Regions; D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics*; D045744:Cell Line, Tumor; D002934:Cinnamates / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000235:genetics*; D011485:Protein Binding; D034622:RNA Interference; D012097:Repressor Proteins / Q000235:genetics*; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D019098:Telomerase / Q000235:genetics / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; C480030:4-(3-(1-adamantyl)-4-hydroxyphenyl)-3-chlorocinnamic acid; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002934:Cinnamates; C569392:MIRN202 microRNA, human; C079439:MXD1 protein, human; D035683:MicroRNAs; D012097:Repressor Proteins; C099683:SIN3A transcription factor; C509186:TERT protein, human; D019098:Telomerase; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D000218:Adamantane
keywords: 3-Cl-AHPC, (E)-4-[3-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid; ARR, Adamantly-substituted retinoid related; HDCA2, histone deacetylase 2; Mxd1, Max dimerization protein 1; Mxd1/Mad1; SAP18; SAP18, Sin3A associated protein 18; Sin3A; c-Myc; hTERT; hTERT, human telomerase reverse transcriptase; miR-202; miR-578; pancreatic cancer