Lee Su-Hyun, Kim Okhwa, Kim Hyo-Jin, Hwangbo Cheol, Lee Jeong-Hyung
Department of Biochemistry, Kangwon National University, Chuncheon, Gangwon-do, 24341, Republic of Korea.
Kangwon Institute of Inclusive Technology (KIIT), Kangwon National University, Chuncheon, Gangwon-do, 24341, Republic of Korea.
Oncogenesis. 2021 Feb 26;10(2):17. doi: 10.1038/s41389-021-00307-0.
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）信号通路在癌细胞增殖和上皮-间质转化（EMT）中的作用已得到充分认识，但其在与其他信号事件相互作用中的贡献却知之甚少。最近的研究表明，TGF-β与Ras信号之间的串扰对TGF-β介导的EMT有贡献。在此，我们证明含Jumonji结构域-3（JMJD3，也称为KDM6B）促进Ras激活的肺癌细胞中TGF-β介导的Smad激活和EMT。肺癌患者中的JMJD3显著增加，并且JMJD3在肺肿瘤组织中的表达尤其与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促进Ras激活的肺癌细胞中TGF-β诱导的Smad激活和EMT，syntenin是一种在配体结合时调节TGF-β受体激活的蛋白质。组织芯片和染色质免疫沉淀分析表明，JMJD3通过直接调节H3K27甲基化水平在表观遗传上诱导syntenin表达。机制探索确定了JMJD3与syntenin在Ras激活的肺癌细胞中调控TGF-β的物理和功能关联。综上所述，这些发现为JMJD3促进syntenin表达从而导致致癌性Ras与TGF-β协同促进EMT的机制提供了新的见解。
