KDM5A and PHF2 positively control expression of pro-metastatic genes repressed by EWS/Fli1, and promote growth and metastatic properties in Ewing sarcoma
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Tyler S. McCann1, Janet K. Parrish1, Joseph Hsieh1,2,3, Marybeth Sechler1,3, Lays M. Sobral1, Chelsea Self4, Kenneth L. Jones4,6, Andrew Goodspeed5,6, James C. Costello5,6 and Paul Jedlicka1,2,3
1 Department of Pathology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
2 Medical Scientist Training Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
3 Cancer Biology Graduate Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
4 Department of Pediatrics, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
5 Department of Pharmacology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
6 Bioinformatics Shared Resource, University of Colorado Cancer Center, Anschutz Medical Campus, Aurora, CO, USA
Keywords: Ewing sarcoma; metastasis; epigenetics; Jumonji-domain histone demethylase
Received: July 22, 2020 Accepted: August 24, 2020 Published: October 27, 2020
Ewing sarcoma is an aggressive malignant neoplasm with high propensity for metastasis and poor clinical outcomes. The EWS/Fli1 oncofusion is the disease driver in > 90% of cases, but presents a difficult therapeutic target. Moreover, EWS/Fli1 plays a complex role in disease progression, with inhibitory effects on critical steps of metastasis. Like many other pediatric cancers, Ewing sarcoma is a disease marked by epigenetic dysregulation. Epigenetic mechanisms present alternative targeting opportunities, but their contributions to Ewing sarcoma metastasis and disease progression remain poorly understood. Here, we show that the epigenetic regulators KDM5A and PHF2 promote growth and metastatic properties in Ewing sarcoma, and, strikingly, activate expression many pro-metastatic genes repressed by EWS/Fli1. These genes include L1CAM, which is associated with adverse outcomes in Ewing sarcoma, and promotes migratory and invasive properties. KDM5A and PHF2 retain their growth promoting effects in more metastatically potent EWS/Fli1low cells, and PHF2 promotes both invasion and L1CAM expression in this cell population. Furthermore, KDM5A and PHF2 each contribute to the increased metastatic potency of EWS/Fli1low cells in vivo. Together, these studies identify KDM5A and PHF2 as novel disease-promoting factors, and potential new targets, in Ewing sarcoma, including the more metastatically potent EWS/Fli1low cell population.
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