Year: 2023
Type: article
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.
Source: Nature Communications
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,290
Awards: G1163075371, G1180749011, G1665110821, G2264348815, Role of Eya3 in regulating the immune microenvironment to promote breast tumor progression, Deciphering Mechanisms by which Tumor Cells Collaborate to Mediate Metastasis, Role of Six1 and the miR106b 25 cluster in EMT and Tumor Progression, Investigating the role of Eya3 in the regulation of innate immune signaling cascades in Triple Negative Breast Cancer, G600082094, G6156078954, G667085813, G6834969422, Mechanism of tumor promotion by the H3K9 histone demethylase KDM3A in Ewing Sarcoma., G8077564701, G8330943367, G9000018383, G9000292995, University of Colorado Cancer Center Support Grant
OpenAlex ID: W4384820529