The role of TOX3 and histone deacetylase inhibitors in embryonal brain tumors

Abstract

Medulloblastoma (MB) is the most common posterior fossa tumor of childhood representing 30% to 40% of tumors in this age group, and one of the most common pediatric solid tumors (15% to 25%). According to the current consensus nomenclature there are four principal molecular subgroups of MB: Wnt, Shh, Group 3 and Group 4. Alterations in Shh pathway affect around 25% of MBs. High-throughput studies have shown a correlation between TOX family member 3 and Shh-driven MB when compared to normal tissue in humans, suggesting that TOX3 gene is up-regulated in these tumors and that it may be important in MB formation and/or tumor maintenance. Similar finding was obtained in a microarray assay of GFAP-Cre+/SmoM2 mouse model versus normal tissue. To date, no studies have examined activities of TOX3 in embryonal brain tumors. I investigated how medulloblastomas are modulated by TOX3, that is whether TOX3 was necessary or sufficient for cerebellar medulloblastoma progression. TOX3 repression in human medulloblastoma models drastically regressed tumor development by blocking cell cycle progression. Induction of TOX3, paradoxically, also impaired tumor growth. This effect has been reported to occur in various oncogenes. Lastly, with an eager to determine new therapeutic drugs for embryonic brain tumor treatment we decided to examine the dependence of tumor formation on HDACs by using the HDACi, panobinostat. HDAC5 and HDAC9 are considered independent factors for poor prognosis. In addition, HDAC1 is associated with Hh signaling pathway through Gli acetylation. Here, we briefly connected TOX3 with the expression of HDAC1. After, confirming the expression of HDAC1 in different embryonic brain tumor samples we demonstrated that panobinostat has strong pharmacological properties against these malignancies not only reducing cell cycle progression, but also promoting cell death. The work presented herein provides several important insights into the pathogenesis of cerebellar medulloblastoma, and may suggest a more general role of TOX3.