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

Jixue Zou; Zhigang Zhou; Liping Wan; Yin Tong; Youwen Qin; Chun Wang; Kun Zhou

doi:10.1371/journal.pone.0136843

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

PLoS One. 2015 Aug 28;10(8):e0136843. doi: 10.1371/journal.pone.0136843. eCollection 2015.

Authors

Jixue Zou¹, Zhigang Zhou², Liping Wan¹, Yin Tong¹, Youwen Qin¹, Chun Wang¹, Kun Zhou¹

Affiliations

¹ Department of Hematology, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai, People's Republic of China.
² Department of Intensive Care Unit, 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Aged
Animals
Azacitidine / analogs & derivatives
Azacitidine / pharmacology
Cell Line, Tumor
Cell Survival / drug effects
Cyclin-Dependent Kinase Inhibitor p15 / genetics
Cyclin-Dependent Kinase Inhibitor p15 / metabolism
DNA Methylation / drug effects
DNA Modification Methylases / pharmacology
Decitabine
Female
Gene Expression Regulation, Neoplastic / drug effects
Hedgehog Proteins / antagonists & inhibitors*
Hedgehog Proteins / genetics*
Humans
Male
Mice
Middle Aged
Myelodysplastic Syndromes / drug therapy*
Myelodysplastic Syndromes / genetics
Myelodysplastic Syndromes / metabolism
Myelodysplastic Syndromes / pathology*
Neoplasm Transplantation
Prognosis
Promoter Regions, Genetic / drug effects
Signal Transduction / drug effects
Transcription Factors / genetics*
Transcription Factors / metabolism
Young Adult
Zinc Finger Protein GLI1

Substances

CDKN2B protein, human
Cyclin-Dependent Kinase Inhibitor p15
GLI1 protein, human
Hedgehog Proteins
SHH protein, human
Transcription Factors
Zinc Finger Protein GLI1
Decitabine
DNA Modification Methylases
Azacitidine

Grants and funding

This work was supported by grants from National Natural Science Foundation of China (grant no. 81200347).