title: miR-326-histone deacetylase-3 feedback loop regulates the invasion and tumorigenic and angiogenic response to anti-cancer drugs.
abstract: Histone modification is known to be associated with multidrug resistance phenotypes. Cancer cell lines that are resistant or have been made resistant to anti-cancer drugs showed lower expression levels of histone deacetylase-3 (HDAC3), among the histone deacetylase(s), than cancer cell lines that were sensitive to anti-cancer drugs. Celastrol and Taxol decreased the expression of HDAC3 in cancer cell lines sensitive to anti-cancer drugs. HDAC3 negatively regulated the invasion, migration, and anchorage-independent growth of cancer cells. HDAC3 conferred sensitivity to anti-cancer drugs in vitro and in vivo. TargetScan analysis predicted miR-326 as a negative regulator of HDAC3. ChIP assays and luciferase assays showed a negative feedback loop between HDAC3 and miR-326. miR-326 decreased the apoptotic effect of anti-cancer drugs, and the miR-326 inhibitor increased the apoptotic effect of anti-cancer drugs. miR-326 enhanced the invasion and migration potential of cancer cells. The miR-326 inhibitor negatively regulated the tumorigenic, metastatic, and angiogenic potential of anti-cancer drug-resistant cancer cells. HDAC3 showed a positive feedback loop with miRNAs such as miR-200b, miR-217, and miR-335. miR-200b, miR-217, and miR-335 negatively regulated the expression of miR-326 and the invasion and migration potential of cancer cells while enhancing the apoptotic effect of anti-cancer drugs. TargetScan analysis predicted miR-200b and miR-217 as negative regulators of cancer-associated gene, a cancer/testis antigen, which is known to regulate the response to anti-cancer drugs. HDAC3 and miR-326 acted upstream of the cancer-associated gene. Thus, we show that the miR-326-HDAC3 feedback loop can be employed as a target for the development of anti-cancer therapeutics.
authors.affiliation: From the Departments of Biochemistry and.
authors.forename: Youngmi
authors.initials: Y
authors.lastname: Kim
authors.affiliation: From the Departments of Biochemistry and.
authors.forename: Hyuna
authors.initials: H
authors.lastname: Kim
authors.affiliation: From the Departments of Biochemistry and.
authors.forename: Hyunmi
authors.initials: H
authors.lastname: Park
authors.affiliation: From the Departments of Biochemistry and.
authors.forename: Deokbum
authors.initials: D
authors.lastname: Park
authors.affiliation: Biological Sciences, College of Natural Sciences, and.
authors.forename: Hansoo
authors.initials: H
authors.lastname: Lee
authors.affiliation: the College of Pharmacy, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Yun Sil
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Graduate School of Medicine, Kangwon National University, Chunchon 200-701 and.
authors.forename: Jongseon
authors.initials: J
authors.lastname: Choe
authors.affiliation: Graduate School of Medicine, Kangwon National University, Chunchon 200-701 and.
authors.forename: Young Myeong
authors.initials: YM
authors.lastname: Kim
authors.affiliation: From the Departments of Biochemistry and jeoungd@kangwon.ac.kr.
authors.forename: Dooil
authors.initials: D
authors.lastname: Jeoung
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D063646:Carcinogenesis / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D025461:Feedback, Physiological / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000099186:Histone Deacetylase 3
chemical_list: D000970:Antineoplastic Agents; D006655:Histone Deacetylases; D035683:MicroRNAs; D000099186:Histone Deacetylase 3; C545322:MIRN326 microRNA, human
keywords: Angiogenesis; Anti-cancer Drug Resistance; Feedback Loop; Gene Expression; Histone Deacetylase 3 (HDAC3); MicroRNA (miRNA); Tumor Metastases; miR-326