Given that Atoh1 is also a putative target of Hh signaling, we conclude that the Hic1 and Ptch1 tumor suppressors cooperate to silence Atoh1 expression during a critical phase in GCP differentiation in which malignant transformation may lead to medulloblastoma.
Because demethylating agents can induce reexpression of silenced tumor suppressors, restoring HIC1 function may present an attractive therapeutic avenue in medulloblastoma by exploiting an apparent addiction to ATOH1.
Given that Atoh1 is also a putative target of Hh signaling, we conclude that the Hic1 and Ptch1 tumor suppressors cooperate to silence Atoh1 expression during a critical phase in GCP differentiation in which malignant transformation may lead to medulloblastoma.
Hypermethylation of the 5'UTR or the central region of HIC1 (or both) was detected in a significant number of MB samples, as well as in cerebellum and neural stem cells.
Recent studies have identified a series of candidate tumor suppressor genes (for example, RASSF1A, CASP8, and HIC1) that are each specifically epigenetically inactivated in a large proportion (> 30%) of medulloblastomas by promoter hypermethylation, leading to the silencing of their gene expression.
The HIC-1 putative tumor-suppressor gene, which exhibits hypermethylation and loss of expression in various tumor entities including medulloblastomas and gliomas, maps to the affected region.
HIC1 methylation was frequent in medulloblastomas (80%, 12 of 15), retinoblastomas (67%, 6 of 9), rhabdomyosarcomas (59%, 13 of 22), germ cell tumors (55%, 6 of 11), and neurouroblastic tumors (36%, 14 of 39); neuroblastomas (43%, 12 of 28); ganglioneuromas (17%, 1 of 6); and ganglioneuroblastomas (20%, 1 of 5).
Therefore, we studied a series of tumor specimens for hypermethylation and deletion of the region containing the HIC-1 gene to determine whether these two mechanisms of gene inactivation play a complimentary role in medulloblastoma.