Medical Scientist Training Program, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
Pharmacology Program, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
Nat Commun. 2023 Jul 19;14(1):4357. doi: 10.1038/s41467-023-39945-w.
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.
尤因肉瘤 (ES) 的特征是存在致癌融合蛋白，如 EWS/FLI1，是一种具有高早期扩散率和远处转移后不良预后的侵袭性儿科恶性肿瘤。在这里，我们证明 SIX1 同源蛋白通过共同调节 EWS/FLI1 靶基因抑制 ES 转移。与 EWS/FLI1 一样，SIX1 促进细胞生长/转化，但显著抑制迁移和侵袭，以及体内转移。我们表明 EWS/FLI1 促进 SIX1 蛋白表达，并且这两种蛋白质具有全基因组结合图谱和转录调节靶标，包括许多与转移相关的基因，如整合素，它们共同调节。我们进一步表明，SIX1 下调整合素对于其抑制侵袭的能力至关重要，这是转移细胞的一个关键特征。这些数据表明 SIX1 通过与 ES 中的关键癌蛋白 EWS/FLI1 进行协调基因调节，具有意外的抗转移功能。
