The epigenetic modifier KDM3A and its downstream target MCAM promote growth and metastasis in Ewing Sarcoma

Abstract

This study aims to explore the roles and mechanisms of new candidates for therapeutic targeting in Ewing Sarcoma. Ewing Sarcoma is an aggressive pediatric malignancy of the bone and soft tissue, driven by EWS/Ets oncogenic fusions and characterized by high propensity for metastasis and poor clinical outcomes. We have identified the Jumonji-domain histone demethylase (JHDM) KDM3A as a novel tumor and metastasis promoter downstream of EWS/Fli1, the most common driver in this disease. Moreover, we have identified the cell surface protein, Melanoma Cell Adhesion Molecule (MCAM), as a potential important mediator of KDM3A action. Our data show that KDM3A and MCAM depletion can each inhibit growth and metastatic phenotypes. Additionally we explore the regulation of MCAM, showing that KDM3A is able to upregulate MCAM expression both through a direct mechanism, as well as indirectly via the Ets1 transcription factor. Analysis of publicly available clinical data shows that Ets1 and MCAM expression levels correlate in Ewing Sarcoma tumors, supporting our mechanistic studies, and, importantly that high MCAM levels are associated with poor survival. KDM3A and MCAM are both therapeutically targetable, and as proof of concept, we find that a pan-JHDM pharmacologic inhibitor can suppress tumorigenesis in vivo. Together, our data identify two new candidate therapeutic targets in Ewing Sarcoma and, importantly, alternatives to drugging of EWS/Ets fusions, which to date has proven very difficult.