Project name: Homo sapiens

Description: The Hedgehog (Hh) signaling pathway regulates normal development and cell proliferation, whereas its aberrant activation causes tumor formation. Hh-induced tumors can arise from different tissues and can be indolent or highly aggressive, such as basal cell carcinoma (BCC) of the skin and neural progenitor-derived medulloblastoma (MB), respectively. Little is known about cell-intrinsic factors that control the development of such diverse Hh-dependent tumors. Transcription factor Zfx is required for the self-renewal of several stem cell types, whereas its role in malignant transformation remains controversial. We found that the deletion of Zfx prevented BCC formation and significantly delayed MB development caused by Hh activation in vivo. In contrast, Zfx was dispensable for the development of Hh-independent brain tumor glioblastoma. We used genome-wide expression and chromatin binding analysis in a human MB cell line to identify direct, evolutionarily conserved targets of Zfx. These targets included the Hh signal transducer Smoothened (Smo), suggesting that Zfx may directly control Hh pathway activation in tumors. Two additional targets of Zfx, Dis3L and Ube2j1, were also required for the growth of MB cells in vitro. These results identify a common cell-intrinsic regulator of diverse Hh-induced tumors, and suggest Zfx and Zfx-controlled genes as possible therapeutic targets in these malignancies.Overall design: Analysis of ZFX binding to chromatin and genomic DNA in the human medulloblastoma cell line DAOY

Data type: Epigenomics

Sample scope: Multiisolate

Relevance: Medical

Last updated: 2013-03-21