EHMT1 mediates cellular motility in embryonal rhabdomyosarcoma by activating SOX8 expression.

BACKGROUND: Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. When metastatic, survival of children with RMS is less than 20% and has remained unchanged over two decades. No targeted drug therapy is available for these cancers. Genomic analysis has revealed a low incidence of somatic mutations in RMS. Epigenetic modifiers thus play important roles in driving oncogenesis. In this study, we examined the role of EHMT1 in fusion- negative embryonal rhabdomyosarcoma (ERMS), the most frequent subtype of RMS. METHODS: We performed transcriptomic and phenotypic analysis in vitro and in vivo using EHMT1 depleted cells as well as that of its target gene SOX8. RESULTS: EHMT1 was found to enhance migration and invasion of ERMS cells in vitro and metastasis in vivo. SOX8, a transcription factor that has key roles in cellular motility was significantly decreased upon EHMT1 loss. Consistently, SOX8 depletion phenotypically mimicked EHMT1 loss. Moreover, RNA Sequencing of SOX8 depleted cells showed down regulation of several integrin genes. Mechanistically, EHMT1 was found to upregulate SOX8 via regulation of BRD4 expression, and consequently increased BRD4 occupancy at the SOX8 promoter. CONCLUSION: Our study reveals a novel EHMT1-SOX8 axis that mediates metastasis in ERMS.