The Hedgehog (Hh) signaling pathway regulates normal development and cell proliferation across the metazoa. Upon its aberrant activation, mammalian Hh signaling can also cause tumor formation. Hh-induced tumors can arise from different tissues and can be locally invasive but rarely metastatic or highly aggressive, as is the case with basal cell carcinoma (BCC) of the skin and the cerebellar tumor medulloblastoma (MB), respectively. Little is known about common cell-intrinsic factors that control the development of such diverse Hh-dependent tumors. The zinc-finger transcription factor Zfx is required for the self-renewal of several stem cell types in both mouse and human, but its role in malignant transformation remains controversial. We found that Zfx is variably required for the development of two distinct Hh-dependent tumors in vivo. Co-deletion of Zfx prevented BCC formation initiated by Hh pathway overactivation in the skin following deletion of the inhibitory receptor Ptch1. Co-deletion of Zfx also delayed development of Hh-dependent MB caused by Ptch1 deletion in vivo. In contrast, Zfx was dispensable for the development of the PTEN-dependent brain tumor glioblastoma, showing that a requirement for Zfx is not generalizable across all cancers. 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). Smo expression data from Zfx-deficient BCC and MB cells in vivo and in vitro suggest that Zfx may directly regulate Hh pathway activation in some cancers. We identified two additional conserved downstream targets of Zfx, Dis3L and Ube2j1, which were required for optimal growth of human MB cells in vitro. These results identify Zfx as a common cell-intrinsic regulator of diverse Hh-induced tumors. Further investigation of the requirement for Zfx and its conserved downstream target genes, such as Dis3L and Ube2j1, in in vivo models of Hh-dependent BCC and MB could lead to the identification of novel targetable molecules for therapies directed against these malignancies.
| Identifer | oai:union.ndltd.org:columbia.edu/oai:academiccommons.columbia.edu:10.7916/D8VQ391B |
| Date | January 2013 |
| Creators | Palmer, Colin James |
| Source Sets | Columbia University |
| Language | English |
| Detected Language | English |
| Type | Theses |
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