Just say no to ATOH: how HIC1 methylation might predispose medulloblastoma to lineage addiction

Abstract

Hypermethylated in cancer-1 (HIC1) is a tumor suppressor frequently targeted for promoter hypermethylation in medulloblastoma, an embryonal tumor of the cerebellum. Recently, we showed that HIC1 is a direct transcriptional repressor of ATOH1, a proneural transcription factor required for normal cerebellar development, as well as for medulloblastoma cell viability. 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.

Figure 1

Simplified representation of the developing cerebellum, showing the relationship between Atoh1 and Hic1 expression in the differentiation of granule neurons. GCPs in the EGL proliferate in response to Shh ligand produced byPurkinje cells (green) and express high levels of Atoh1 (red) driven byactivation of the Hh pathway. Hic1 (blue) is expressed bycells lining the inner EGL, and more strongly as the differentiating postmitotic granule cells migrate down the Bergmann glia through the molecular layer (ML) and Purkinje cell layer (PCL), to the IGL. Hic1 directlyrepresses transcription of Atoh1 in maturing granule cells downstream of the Hh pathway, making them unable to respond to high concentrations of Shh in the PCL.