wizyta

od 2020-09-20

Title: Heme oxygenase-1 controls an HDAC4-MIR-206 pathway of oxidative stress in rhabdomyosarcoma

Source: Cancer Research

Year : 2016

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. © 2016 AACR.

DOI: 10.1158/0008-5472.CAN-15-1883   (Pobrane:  2022-10-13)