KDM3A/Ets1/MCAM axis promotes growth and metastatic properties in Rhabdomyosarcoma
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https://doi.org/10.18632/genesandcancer.200
Lays Martin Sobral1, Marybeth Sechler1,2, Janet K. Parrish1, Tyler S. McCann1, Kenneth L. Jones3, Joshua C. Black4 and Paul Jedlicka1,2
1 Department of Pathology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
2 Cancer Biology Graduate Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
3 Department of Pediatrics, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
4 Department of Pharmacology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
Correspondence:
Paul Jedlicka, email:
Keywords: pediatric cancer, rhabdomyosarcoma, KDM3A, Ets1, metastasis
Received: November 27, 2019 Accepted: February 01, 2020 Published: February 11, 2020
Abstract
Rhabdomyosarcoma (RMS) is the most common soft tissue malignancy of childhood. RMS exists as two major disease subtypes, with oncofusion-positive RMS (FP-RMS) typically carrying a worse prognosis than oncofusion-negative RMS (FN-RMS), in part due to higher propensity for metastasis. Epigenetic mechanisms have recently emerged as critical players in the pathogenesis of pediatric cancers, as well as potential new therapeutic vulnerabilities. Herein, we show that the epigenetic regulator KDM3A, a member of the Jumonji-domain histone demethylase (JHDM) family, is overexpressed, potently promotes colony formation and transendothelial invasion, and activates the expression of genes involved in cell growth, migration and metastasis, in both FN-RMS and FP-RMS. In mechanistic studies, we demonstrate that both RMS subtypes utilize a KDM3A/Ets1/MCAM disease-promoting axis recently discovered in Ewing Sarcoma, another aggressive pediatric cancer of distinct cellular and molecular origin. We further show that KDM3A depletion in FP-RMS cells inhibits both tumor growth and metastasis in vivo, and that RMS cells are highly sensitive to colony growth inhibition by the pan-JHDM inhibitor JIB-04. Together, our studies reveal an important role for the KDM3A/Ets1/MCAM axis in pediatric sarcomas of distinct cellular and molecular ontogeny, and identify new targetable vulnerabilities in RMS.
