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The histone demethylase KDM3A, and its downstream target MCAM, promote Ewing Sarcoma cell migration and metastasis

Oncogene volume 36, pages 4150–4160 (2017)Cite this article

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Abstract

Ewing Sarcoma is the second most common solid pediatric malignant neoplasm of bone and soft tissue. Driven by EWS/Ets, or rarely variant, oncogenic fusions, Ewing Sarcoma is a biologically and clinically aggressive disease with a high propensity for metastasis. However, the mechanisms underpinning Ewing Sarcoma metastasis are currently not well understood. In the present study, we identify and characterize a novel metastasis-promotional pathway in Ewing Sarcoma, involving the histone demethylase KDM3A, previously identified by our laboratory as a new cancer-promoting gene in this disease. Using global gene expression profiling, we show that KDM3A positively regulates genes and pathways implicated in cell migration and metastasis, and demonstrate, using functional assays, that KDM3A promotes migration in vitro and experimental, post-intravasation, metastasis in vivo. We further identify the melanoma cell adhesion molecule (MCAM) as a novel KDM3A target gene in Ewing Sarcoma, and an important effector of KDM3A pro-metastatic action. Specifically, we demonstrate that MCAM depletion, like KDM3A depletion, inhibits cell migration in vitro and experimental metastasis in vivo, and that MCAM partially rescues impaired migration due to KDM3A knock-down. Mechanistically, we show that KDM3A regulates MCAM expression both through a direct mechanism, involving modulation of H3K9 methylation at the MCAM promoter, and an indirect mechanism, via the Ets1 transcription factor. Finally, we identify an association between high MCAM levels in patient tumors and poor survival, in two different Ewing Sarcoma clinical cohorts. Taken together, our studies uncover a new metastasis-promoting pathway in Ewing Sarcoma, with therapeutically targetable components.

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Acknowledgements

We wish to thank Elizabeth Wellberg for assistance with gene expression profiling studies; members of the Tobias Neff and Kathrin Bernt laboratories for assistance with ChIP studies; Elizabeth Lawlor at the University of Michigan for the TC32 cell line, and tumor expression profiling and patient outcome data; and Steve Lessnick at Nationwide Children’s Hospital for retroviral packaging constructs. We further wish to thank the University of Colorado Cancer Center Flow Cytometry, Functional Genomics, Tissue Culture, DNA Sequencing and Small Animal Imaging Core Facilities, supported by P30-CA046934. Funding support for this work was provided by the Front Range Cancer Challenge, Children’s Hospital Colorado Research Institute, University of Colorado School of Medicine Academic Enrichment Funds, and R01-CA183874 (PJ); the Cancer League of Colorado (PJ and MS); and F31-CA203053 (MS).

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Authors and Affiliations

  1. Cancer Biology Graduate Training Program,

    M Sechler & P Jedlicka

  2. University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA

    M Sechler, J K Parrish, D K Birks & P Jedlicka

  3. Department of Pathology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA

    J K Parrish & P Jedlicka

  4. Department of Neurosurgery, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA

    D K Birks

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Sechler, M., Parrish, J., Birks, D. et al. The histone demethylase KDM3A, and its downstream target MCAM, promote Ewing Sarcoma cell migration and metastasis. Oncogene 36, 4150–4160 (2017). https://doi.org/10.1038/onc.2017.44

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