Background: While developing a differentiation therapy for Sonic Hedgehog Medulloblastoma (MB), we discovered a potential paradoxical feedback cycle between Ezh2, a protein that temporarily keeps differentiation genes silenced via trimethylating H3K27, and Cyclin D1, a protein that regulates cell cycle entry. Methods: We quantified H3K27me3 in P7 purified cerebral GNPs using chromatin immunoprecipitation sequencing and correlated it with gene expression via RNA sequencing (RNAseq). To assess transcriptional effects of Ezh2 loss, we purified P7 GNPs from Math1-Cre, Ezh2-flox knockout mice. MB cells were cultured in suspension spheres and imaged using the ImageXpress Micro XLS system, with nuclei segmented based on DAPI staining. Results: Cyclin D1 ranked among the top 7.37% of expressed genes but was heavily marked by the repressive histone mark H3K27me3 (top 5.5%) in GNPs. Ezh2 overexpression increased G0-arrested MB cells 2.7-fold, while, in GNPs, RNAseq showed significant Cyclin D1 upregulation in Ezh2 knockout mice (Log2FC: 1.301). Cyclin D1 regulates the pRb/E2F1 complex, and we observe that Ezh2 expression depends on pRb/E2F1 complex abundance, forming a feedback loop. Notably, combining the Hedgehog inhibitor Vismodegib with an Ezh2 inhibitor rescued MB cells from Vismodegib-induced death. Conclusions: Our study introduces a model that promotes GNP differentiation, leading tumor cells to differentiate into neurons.