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      Heme Oxygenase-1 Controls an HDAC4-miR-206 Pathway of Oxidative Stress in Rhabdomyosarcoma.

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          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.

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          Author and article information

          Journal
          Cancer Res.
          Cancer research
          American Association for Cancer Research (AACR)
          1538-7445
          0008-5472
          Oct 01 2016
          : 76
          : 19
          Affiliations
          [1 ] Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
          [2 ] Department of Oncology, Hematology and Bone Marrow Transplantation, Wroclaw Medical University, Wroclaw, Poland.
          [3 ] 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.
          [4 ] Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland. alicja.jozkowicz@uj.edu.pl.
          Article
          0008-5472.CAN-15-1883
          10.1158/0008-5472.CAN-15-1883
          27488535
          c69dad07-924e-4d59-9f85-c2b33dfd6510
          History

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