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Stimulating BMP4 signaling via HDAC11 inhibition suppresses malignancy in preclinical models of human neuroblastoma

ABSTRACT: Bone morphogenetic proteins (BMPs) trigger as cell-extrinsic signals the differentiation of neural crest progenitor cells to the sympathoadrenal cell lineage. Human neuroblastoma derives from aberrant neural crest progenitor cells. We here show that histone deacetylase 11 (HDAC11), the most recently identified family member with, as yet, largely unknown function, is recruited to the BMP4 gene promoter and represses its transcription in neuroblastoma. Both HDAC11 depletion and enzymatic inhibition revert the epigenetic silencing of BMP4, thereby blocking a critical oncogenic function of HDAC11. Activated BMP4 signaling through targeting of HDAC11 induces a transcriptional profile predictive of favorable prognosis for patients when expressed in the tumors, indicating that the HDAC11-BMP4 axis plays a critical role for neuroblastoma biology. Furthermore, pathway activation causes MYCN proto-oncogene repression on a molecular level and anti-proliferative effects in functional assays in neuroblastoma cell lines and primary sphere cultures as well as strongly inhibiting tumor formation and growth of subcutaneous neuroblastoma xenografts in mice. For high-risk neuroblastoma, with cure rates below 30% using current treatment strategies, our work suggests a novel targeted therapeutic approach that would reactivate the developmental pathway inducing normal differentiation of neural crest progenitor cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE20399 | GEO | 2014/12/31

SECONDARY ACCESSION(S): PRJNA125531

REPOSITORIES: GEO

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Project description:Neuroblastoma is an embryonal tumor which originates from neural crest progenitor cells that fail to differentiate along their predefined route to sympathetic neurons or sympatho-adrenergic adrenal cells. It is the most common extracranial tumor of childhood and accounts for 15% of all childhood cancer deaths. Especially patients suffering from high grade or relapsed neuroblastoma have poor outcome in spite of aggressive treatment regimens including autologous stem cell transplantation. Those patients are in urgent need of additional effective therapies which demands the development of targeted approaches. Dihydroorotatedehydrogenase (DHODH) is the fourth enzyme of the pyrimidine synthesis pathway which oxidizes dihydroorotate to orotate. In recent past it became a potential drug target for cancer treatment because of its keyrole in processing essential pyrimidine nucleotides. On the basis of the existing data, functional inhibition of DHODH is considered to be promising therapeutic option for several tumor entities like advanced colorectal, breast or lung-cancers. Leflunomide is an established drug in treatment of the autoimmune diseases rheumatoid arthritis and multiple sclerosis. In the liver Leflunomide becomes converted to its active metabolite called Teriflunomide, which inhibits the activity of DHODH directly. In recent times Leflunomide is also used for therapy against the Cytomegalovirus and the BK virus. Also for Melanoma was shown recently a decreased growth rate due to Leflunomide treatment in a zebrafish and a mouse model. As Melanoma is a malignant tumor of the skin, which derives also from neural crest progenitor cells, a coherent investigation of effictivity of Leflunomide in neuroblastoma celllines showed first promising results. The aim of our study was to reanalyse the effectivity of Leflunomide in Neuroblastoma and to shed further light in its biological mode of action. Three+B52 biological samples of the human neuroblastoma cell line IMR32 were treated with DMSO or Teriflunomide [118 ￂﾵM]

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Stimulating BMP4 signaling via HDAC11 inhibition suppresses malignancy in preclinical models of human neuroblastoma

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