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Targeting the Sonic Hedgehog-Gli1 Pathway as a Potential New Therapeutic Strategy for Myelodysplastic Syndromes
Jixue Zou1, Zhigang Zhou2, Liping Wan1
1Department of Hematology, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai, People's Republic of China.
Abstract:
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.
Insights
The Shh signaling pathway is active in myelodysplastic syndrome (MDS) and drives disease progression. Inhibiting Gli1, a key component, halts MDS cell growth and enhances the efficacy of 5-azacytidine therapy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Myelodysplastic syndrome (MDS) pathogenesis involves complex signaling pathway dysregulations.
- Identifying specific biomarkers and therapeutic targets is crucial for novel MDS treatments.
Purpose of the Study:
- To investigate the role of the Shh signaling pathway in MDS pathogenesis and progression.
- To evaluate Gli1 as a potential therapeutic target for MDS.
Main Methods:
- Assessed Shh signaling pathway activity in MDS patient samples.
- Performed in vitro and in vivo knockdown of Gli1.
- Analyzed cell proliferation, apoptosis, and cell cycle phase distribution.
- Investigated the effect of Gli1 silencing on p15 gene expression and DNA methylation.
Main Results:
- The Shh signaling pathway is active in MDS and correlates with disease progression.
- Gli1 knockdown inhibited MDS cell proliferation (in vitro and in vivo), induced apoptosis, and caused G0/G1 phase arrest.
- Gli1 silencing enhanced 5-aza-2'-deoxycytidine's demethylating effect on the p15 gene promoter by inhibiting DNMT1, thereby promoting p15 expression.
Conclusions:
- The Shh signaling pathway is implicated in MDS pathogenesis and progression through modulation of DNA methylation.
- Gli1 inhibition represents a potential therapeutic strategy to enhance 5-azacytidine treatment efficacy in MDS.
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