Novel Downstream Effectors of Mitogenic Sonic Hedgehog Signaling in Cerebellar Development and Sonic Hedgehog Medulloblastoma translation missing: es.hyrax.visibility.toc_restricted.text

Robinson, Mary Hope (Fall 2018)

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The most common central nervous system malignancy in children, medulloblastoma arises from neural progenitor cells in the cerebellum and is diagnosed in over 300 children each year in the United States. While the current standard of care has brought the survival rate to ~70%, the treatments often leave patients with long-term negative side effects. The need for therapeutics that are specific, effective, and less toxic requires a greater understanding of the molecular underpinnings of medulloblastoma. Sonic Hedgehog (SHH) medulloblastoma, driven by aberrant activation of the SHH pathway, constitutes ~30% of cases and is the focus of this work. The major components of the SHH pathway have been identified, but there is still much to learn about the downstream effectors.

Pediatric cancers have few genetic mutations, providing a relatively uncluttered background to dissect molecular signaling pathways. At the same time, this paucity of mutations presents few targets and has led researchers to look beyond mutations. Epigenetics, changes in gene expression without changes in DNA sequence, has become an important avenue for research. We have identified Helicase, Lymphoid Specific (HELLS) as an epigenetic factor that is upregulated downstream of the SHH pathway in SHH-N stimulated CGNPs, in the developing murine cerebellum, and in both human and murine SHH MB when compared to non-tumor cerebellar tissue. HELLS upregulation was modulated by inhibition of the interaction between TEAD, a transcription factor, and the oncogenic co-activator YAP1, an established downstream effector of SHH. To ascertain direct regulation of HELLS by YAP/TEAD, a ChIP-qPCR assay was utilized, revealing YAP1 binding to Hells upstream DNA. These results indicate YAP1 mediates the SHH induced upregulation of HELLS in our systems. Because epigenetic modifications can be reversed, identification of an epigenetic factor upregulated by the SHH signaling pathway in medulloblastoma could have important implications for future therapeutics, not only in SHH MB but also in the myriad of other cancers with aberrant SHH signaling. 

In a separate project, we have identified high levels of HIF1α protein downstream of SHH signaling in CGNPs cultured in normoxic conditions. Rather than increased transcription, our results indicate stabilization of HIF1α, likely through ROS signaling. In addition, we identified increased levels of NOX4 protein, a potent producer of ROS. Taken together, our results demonstrate increased HIF1α protein levels as a result of ROS signaling induced stabilization. Similar to epigenetic regulation, ROS levels can be modulated, presenting an intriguing possibility for therapeutics development.

These studies lay the foundation for further research and may help fill in some of the gaps between SHH signaling and tumor formation. Importantly, both of these avenues of research could result in targeted therapies to treat SHH MB.

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