Transforming growth factor-β (TGF-β) signaling pathways are well-recognized for their role in proliferation and epithelial–mesenchymal transition (EMT) of cancer cells, but much less is understood about their contribution to interactions with other signaling events. Recent studies have indicated that crosstalk between TGF-β and Ras signaling makes a contribution to TGF-β-mediated EMT. Here, we demonstrate that Jumonji domain containing-3 (JMJD3 also called KDM6B) promotes TGF-β-mediated Smad activation and EMT in Ras-activated lung cancer cells. JMJD3 in lung cancer patients was significantly increased and JMJD3 expression in lung tumor tissues was correlated with expression of K-Ras or H-Ras in particular, and its expression was regulated by Ras activity in lung cancer cells. JMJD3 promotes TGF-β-induced Smad activation and EMT in Ras-activated lung cancer cells through the induction of syntenin, a protein that regulates TGF-β receptor activation upon ligand binding. Tissue array and ChIP analysis revealed that JMJD3 epigenetically induces syntenin expression by directly regulating H3K27 methylation levels. Mechanical exploration identified a physical and functional association of JMJD3 with syntenin presiding over the TGF-β in Ras-activated lung cancer cells. Taken together, these findings provide new insight into the mechanisms by which JMJD3 promotes syntenin expression resulting in oncogenic Ras cooperation with TGF-β to promote EMT.

转化生长因子-β（TGF-β）信号通路在癌细胞的增殖和上皮-间充质转化（EMT）中的作用已广为人知，但对其与其他信号事件相互作用的贡献了解甚少。最近的研究表明，TGF-β和Ras信号之间的串扰对TGF-β介导的EMT有所贡献。在这里，我们证明了含有Jumonji结构域的3（JMJD3也称为KDM6B）在Ras激活的肺癌细胞中促进TGF-β介导的Smad激活和EMT。肺癌患者的JMJD3显着增加，特别是肺癌组织中JMJD3的表达与K-Ras或H-Ras的表达相关，其表达受肺癌细胞中Ras活性的调节。JMJD3通过诱导syntenin来促进Ras激活的肺癌细胞中TGF-β诱导的Smad激活和EMT激活，syntenin是一种在配体结合后调节TGF-β受体激活的蛋白。组织阵列和ChIP分析表明，JMJD3通过直接调节H3K27甲基化水平，在表观遗传学上诱导合成素表达。机械探索确定了JMJD3与在Ras激活的肺癌细胞中主导TGF-β的syntenin的物理和功能联系。综上所述，这些发现为JMJD3促进syntenin表达的机制提供了新的见解，从而导致致癌性Ras与TGF-β协同促进EMT。组织阵列和ChIP分析表明，JMJD3通过直接调节H3K27甲基化水平，在表观遗传学上诱导合成素表达。机械探索确定了JMJD3与在Ras激活的肺癌细胞中主导TGF-β的syntenin的物理和功能联系。综上所述，这些发现为JMJD3促进syntenin表达的机制提供了新的见解，从而导致致癌性Ras与TGF-β协同促进EMT。组织阵列和ChIP分析表明，JMJD3通过直接调节H3K27甲基化水平，在表观遗传学上诱导合成素表达。机械探索确定了JMJD3与在Ras激活的肺癌细胞中主导TGF-β的syntenin的物理和功能联系。综上，这些发现为JMJD3促进Syntenin表达的机制提供了新的见解，从而导致致癌性Ras与TGF-β协同促进EMT。