SIX1 and EWS/FLI1 co-regulate an anti-metastatic gene network in Ewing Sarcoma

Connor J. Hughes, Kaiah M. Fields, Etienne P. Danis, Jessica Y. Hsu, Deepika Neelakantan, Melanie Y. Vincent, Annika L. Gustafson, Michael J. Oliphant, Varsha Sreekanth, Vadym Zaberezhnyy, James C. Costello, Paul Jedlicka and Heide L. Ford ()
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Connor J. Hughes: University of Colorado Anschutz Medical Campus
Kaiah M. Fields: University of Colorado Anschutz Medical Campus
Etienne P. Danis: University of Colorado Anschutz Medical Campus
Jessica Y. Hsu: University of Colorado Anschutz Medical Campus
Deepika Neelakantan: University of Colorado Anschutz Medical Campus
Melanie Y. Vincent: University of Colorado Anschutz Medical Campus
Annika L. Gustafson: University of Colorado Anschutz Medical Campus
Michael J. Oliphant: University of Colorado Anschutz Medical Campus
Varsha Sreekanth: University of Colorado Anschutz Medical Campus
Vadym Zaberezhnyy: University of Colorado Anschutz Medical Campus
James C. Costello: University of Colorado Anschutz Medical Campus
Paul Jedlicka: University of Colorado Anschutz Medical Campus
Heide L. Ford: University of Colorado Anschutz Medical Campus

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract Ewing sarcoma (ES), which is characterized by the presence of oncogenic fusion proteins such as EWS/FLI1, is an aggressive pediatric malignancy with a high rate of early dissemination and poor outcome after distant spread. Here we demonstrate that the SIX1 homeoprotein, which enhances metastasis in most tumor types, suppresses ES metastasis by co-regulating EWS/FLI1 target genes. Like EWS/FLI1, SIX1 promotes cell growth/transformation, yet dramatically inhibits migration and invasion, as well as metastasis in vivo. We show that EWS/FLI1 promotes SIX1 protein expression, and that the two proteins share genome-wide binding profiles and transcriptional regulatory targets, including many metastasis-associated genes such as integrins, which they co-regulate. We further show that SIX1 downregulation of integrins is critical to its ability to inhibit invasion, a key characteristic of metastatic cells. These data demonstrate an unexpected anti-metastatic function for SIX1, through coordinate gene regulation with the key oncoprotein in ES, EWS/FLI1.

Date: 2023
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DOI: 10.1038/s41467-023-39945-w

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