ID #486 JMJD6 as a Novel Target in Group 3 (MYC-driven) Medulloblastoma

Abstract

Group 3 (MYC-driven) medulloblastoma (MB) is a highly aggressive brain tumor with poor prognosis and limited treatment options. While the MYC oncogene is established as the oncogenic driver in Group 3 MB, it has remained undruggable. Thus, targeting regulatory components of MYC and the signaling pathways regulated by it is of great potential therapeutic value. Studies have revealed that MB has very few germline mutations in cancer predisposition genes, suggesting that dysregulated epigenetic pathways might be critical in MB pathogenesis. Particularly, dysregulation of epigenetic modifiers, including histone methyltransferases and histone demethylases, is very common in Group 3 MB, compared to other MB subgroups. Therefore, it is important to identify epigenetic modifiers that may have controls on MYC and its tumorigenic activities and explore these as the epigenetic drug-candidate targets in Group 3 MB. In this regard, we found that protein arginine demethylase Jumonji-C-domain-containing-protein 6 (JMJD6), an emerging key epigenetic enzyme in cancers, is a novel regulator of MYC expression in MYC-driven MB. We observed high levels of JMJD6 that not only mirror MYC expression in the most aggressive MB but also correlate with poor outcomes in these patients. Pharmacogenetic inhibition of JMJD6 decreased MYC expression, cellular proliferation/survival and stemness in MYC-amplified MB cells. Mechanistically, our results revealed that JMJD6 forms complexes with BRD4 and binds to the MYC promoter, suggesting that JMJD6 can regulate MYC at the transcription level. Indeed, our transcriptomics analysis showed that JMJD6 inhibition suppresses MYC-target genes and its induced transcriptional programs in MYC-amplified MB cells.Moreover, our in vivo analyses of JMJD6 inhibition, either with inducible gene knockdown or a pharmacologic small molecule inhibitor, demonstrated anti-MB potential with suppressed MYC expression. Overall, our findings establish a functional link between JMJD6 and MYC-mediated transcriptional regulation, suggesting a promising therapeutic approach targeting JMJD6-MYC axis for MYC-driven MB.