SIX1 and EWS/FLI1 co-regulate an anti-metastatic gene network in Ewing Sarcoma.
In: Nature Communications, Jg. 14 (2023-07-19), Heft 1, S. 1-19
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Zugriff:
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. The tumour-specific functions of SIX1 homeoprotein in Ewing sarcoma (ES) remain poorly understood. Here, the authors suggest that SIX1, which enhances metastasis in most tumour types, suppresses ES metastasis by co-regulating EWS/FLI1 target genes. [ABSTRACT FROM AUTHOR]
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SIX1 and EWS/FLI1 co-regulate an anti-metastatic gene network in Ewing Sarcoma.
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Autor/in / Beteiligte Person: | Hughes, Connor J. ; Fields, Kaiah M. ; Danis, Etienne P. ; Hsu, Jessica Y. ; Neelakantan, Deepika ; Vincent, Melanie Y. ; Gustafson, Annika L. ; Oliphant, Michael J. ; Sreekanth, Varsha ; Zaberezhnyy, Vadym ; Costello, James C. ; Jedlicka, Paul ; Ford, Heide L. |
Zeitschrift: | Nature Communications, Jg. 14 (2023-07-19), Heft 1, S. 1-19 |
Veröffentlichung: | 2023 |
Medientyp: | academicJournal |
ISSN: | 2041-1723 (print) |
DOI: | 10.1038/s41467-023-39945-w |
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