title: Targeting the Sonic Hedgehog-Gli1 Pathway as a Potential New Therapeutic Strategy for Myelodysplastic Syndromes.
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.
authors: Department of Hematology, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai, People's Republic of China.
authors: Jixue
authors: J
authors: Zou
authors: Department of Intensive Care Unit, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai, People's Republic of China.
authors: Zhigang
authors: Z
authors: Zhou
authors: Department of Hematology, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai, People's Republic of China.
authors: Liping
authors: L
authors: Wan
authors: Department of Hematology, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai, People's Republic of China.
authors: Yin
authors: Y
authors: Tong
authors: Department of Hematology, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai, People's Republic of China.
authors: Youwen
authors: Y
authors: Qin
authors: Department of Hematology, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai, People's Republic of China.
authors: Chun
authors: C
authors: Wang
authors: Department of Hematology, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai, People's Republic of China.
authors: Kun
authors: K
authors: Zhou
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D015254:DNA Modification Methylases / Q000494:pharmacology; D000077209:Decitabine; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009368:Neoplasm Transplantation; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult; D000071676:Zinc Finger Protein GLI1
chemical_list: C493966:CDKN2B protein, human; D050762:Cyclin-Dependent Kinase Inhibitor p15; C400551:GLI1 protein, human; D053823:Hedgehog Proteins; C509239:SHH protein, human; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D000077209:Decitabine; D015254:DNA Modification Methylases; D001374:Azacitidine