title: Heme Oxygenase-1 Controls an HDAC4-miR-206 Pathway of Oxidative Stress in Rhabdomyosarcoma.
abstract: Rhabdomyosarcoma (RMS) is an aggressive soft tissue cancer characterized by disturbed myogenic differentiation. Here we report a role for the oxidative stress response factor HO-1 in progression of RMS. We found that HO-1 was elevated and its effector target miR-206 decreased in RMS cell lines and clinical primary tumors of the more aggressive alveolar phenotype (aRMS). In embryonal RMS (eRMS), HO-1 expression was induced by Pax3/7-FoxO1, an aRMS hallmark oncogene, followed by a drop in miR-206 levels. Inhibition of HO-1 by tin protoporphyrin (SnPP) or siRNA downregulated Pax3/7-FoxO1 target genes and induced a myogenic program in RMS. These effects were not mediated by altered myoD expression; instead, cells with elevated HO-1 produced less reactive oxygen species, resulting in nuclear localization of HDAC4 and miR-206 repression. HO-1 inhibition by SnPP reduced growth and vascularization of RMS tumors in vivo accompanied by induction of miR-206. Effects of SnPP on miR-206 expression and RMS tumor growth were mimicked by pharmacologic inhibition of HDAC. Thus, HO-1 inhibition activates an miR-206-dependent myogenic program in RMS, offering a novel therapeutic strategy for treatment of this malignancy. Cancer Res; 76(19); 5707-18. ©2016 AACR.
authors.affiliation: Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Ciesla
authors.affiliation: Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
authors.forename: Paulina
authors.initials: P
authors.lastname: Marona
authors.affiliation: Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Kozakowska
authors.affiliation: Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
authors.forename: Mateusz
authors.initials: M
authors.lastname: Jez
authors.affiliation: Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
authors.forename: Marta
authors.initials: M
authors.lastname: Seczynska
authors.affiliation: Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Loboda
authors.affiliation: Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
authors.forename: Karolina
authors.initials: K
authors.lastname: Bukowska-Strakova
authors.affiliation: Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
authors.forename: Agata
authors.initials: A
authors.lastname: Szade
authors.affiliation: Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Walawender
authors.affiliation: Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Kusior
authors.affiliation: Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
authors.forename: Jacek
authors.initials: J
authors.lastname: Stepniewski
authors.affiliation: Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Szade
authors.affiliation: Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
authors.forename: Bart
authors.initials: B
authors.lastname: Krist
authors.affiliation: Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
authors.forename: Oleksandr
authors.initials: O
authors.lastname: Yagensky
authors.affiliation: Department of Oncology, Hematology and Bone Marrow Transplantation, Wroclaw Medical University, Wroclaw, Poland.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Urbanik
authors.affiliation: Department of Oncology, Hematology and Bone Marrow Transplantation, Wroclaw Medical University, Wroclaw, Poland.
authors.forename: Bernarda
authors.initials: B
authors.lastname: Kazanowska
authors.affiliation: Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland. International Associated Laboratory, Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland.
authors.forename: Jozef
authors.initials: J
authors.lastname: Dulak
authors.affiliation: Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland. alicja.jozkowicz@uj.edu.pl.
authors.forename: Alicja
authors.initials: A
authors.lastname: Jozkowicz
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D000071161:Forkhead Box Protein O1 / Q000235:genetics; D050939:Gene Fusion; D051547:Heme Oxygenase-1 / Q000502:physiology*; D006655:Histone Deacetylases / Q000502:physiology*; D006801:Humans; D008665:Metalloporphyrins / Q000494:pharmacology; D051379:Mice; D035683:MicroRNAs / Q000502:physiology*; D018384:Oxidative Stress; D000072041:PAX3 Transcription Factor / Q000235:genetics; D011524:Protoporphyrins / Q000494:pharmacology; D012097:Repressor Proteins / Q000502:physiology*; D012208:Rhabdomyosarcoma / Q000378:metabolism*
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; C546087:MIRN206 microRNA, human; D008665:Metalloporphyrins; D035683:MicroRNAs; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D011524:Protoporphyrins; D012097:Repressor Proteins; C032628:tin protoporphyrin IX; D051547:Heme Oxygenase-1; C400300:HDAC4 protein, human; D006655:Histone Deacetylases