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Targeting the Sonic Hedgehog-Gli1 Pathway as a Potential New Therapeutic Strategy for Myelodysplastic Syndromes

The complex mechanistic array underlying the pathogenesis of myelodysplastic syndrome (MDS) is still unclear. Although dysregulations of different signaling pathways involved in MDS have been described, the identification of specific biomarkers and therapy targets remains an important task in order...

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Autores principales: Zou, Jixue, Zhou, Zhigang, Wan, Liping, Tong, Yin, Qin, Youwen, Wang, Chun, Zhou, Kun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4552723/
https://www.ncbi.nlm.nih.gov/pubmed/26317501
http://dx.doi.org/10.1371/journal.pone.0136843
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author Zou, Jixue
Zhou, Zhigang
Wan, Liping
Tong, Yin
Qin, Youwen
Wang, Chun
Zhou, Kun
author_facet Zou, Jixue
Zhou, Zhigang
Wan, Liping
Tong, Yin
Qin, Youwen
Wang, Chun
Zhou, Kun
author_sort Zou, Jixue
collection PubMed
description The complex mechanistic array underlying the pathogenesis of myelodysplastic syndrome (MDS) is still unclear. Although dysregulations of different signaling pathways involved in MDS have been described, the identification of specific biomarkers and therapy targets remains an important task in order to establish novel therapeutic approaches. Here, we demonstrated that the Shh signaling pathway is active in MDS and correlated it with disease progression. Additionally, the knockdown of Gli1 significantly inhibited cell proliferation in vitro and in vivo. Gli1 silencing also induced apoptosis and G0/G1 phase arrest. Furthermore, Gli1 silencing enhanced the demethylating effect of 5-aza-2'-deoxycytidine on the p15 gene promoter and subsequently promoted its expression by inhibiting DNA methyltransferase 1(DNMT1). Our findings show that the Shh signaling pathway plays a role in the pathogenesis and disease progression of MDS, and proceeds by modulating DNA methylation. This pathway may prove to be a potential therapeutic target for enhancing the therapeutic effects of 5-azacytidine on malignant transformation of MDS.
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spelling pubmed-45527232015-09-10 Targeting the Sonic Hedgehog-Gli1 Pathway as a Potential New Therapeutic Strategy for Myelodysplastic Syndromes Zou, Jixue Zhou, Zhigang Wan, Liping Tong, Yin Qin, Youwen Wang, Chun Zhou, Kun PLoS One Research Article The complex mechanistic array underlying the pathogenesis of myelodysplastic syndrome (MDS) is still unclear. Although dysregulations of different signaling pathways involved in MDS have been described, the identification of specific biomarkers and therapy targets remains an important task in order to establish novel therapeutic approaches. Here, we demonstrated that the Shh signaling pathway is active in MDS and correlated it with disease progression. Additionally, the knockdown of Gli1 significantly inhibited cell proliferation in vitro and in vivo. Gli1 silencing also induced apoptosis and G0/G1 phase arrest. Furthermore, Gli1 silencing enhanced the demethylating effect of 5-aza-2'-deoxycytidine on the p15 gene promoter and subsequently promoted its expression by inhibiting DNA methyltransferase 1(DNMT1). Our findings show that the Shh signaling pathway plays a role in the pathogenesis and disease progression of MDS, and proceeds by modulating DNA methylation. This pathway may prove to be a potential therapeutic target for enhancing the therapeutic effects of 5-azacytidine on malignant transformation of MDS. Public Library of Science 2015-08-28 /pmc/articles/PMC4552723/ /pubmed/26317501 http://dx.doi.org/10.1371/journal.pone.0136843 Text en © 2015 Zou et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Zou, Jixue
Zhou, Zhigang
Wan, Liping
Tong, Yin
Qin, Youwen
Wang, Chun
Zhou, Kun
Targeting the Sonic Hedgehog-Gli1 Pathway as a Potential New Therapeutic Strategy for Myelodysplastic Syndromes
title Targeting the Sonic Hedgehog-Gli1 Pathway as a Potential New Therapeutic Strategy for Myelodysplastic Syndromes
title_full Targeting the Sonic Hedgehog-Gli1 Pathway as a Potential New Therapeutic Strategy for Myelodysplastic Syndromes
title_fullStr Targeting the Sonic Hedgehog-Gli1 Pathway as a Potential New Therapeutic Strategy for Myelodysplastic Syndromes
title_full_unstemmed Targeting the Sonic Hedgehog-Gli1 Pathway as a Potential New Therapeutic Strategy for Myelodysplastic Syndromes
title_short Targeting the Sonic Hedgehog-Gli1 Pathway as a Potential New Therapeutic Strategy for Myelodysplastic Syndromes
title_sort targeting the sonic hedgehog-gli1 pathway as a potential new therapeutic strategy for myelodysplastic syndromes
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4552723/
https://www.ncbi.nlm.nih.gov/pubmed/26317501
http://dx.doi.org/10.1371/journal.pone.0136843
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