MED1 Downregulation Contributes to TGFb-Induced Metastasis by Inhibiting SMAD2 Ubiquitination Degradation in Cutaneous Melanoma
MED1 Downregulation Contributes to TGFb-Induced Metastasis by Inhibiting SMAD2 Ubiquitination Degradation in Cutaneous Melanoma
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DOI：
10.1016/j.jid.2022.01.013
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发表时间：
2022-07-20
影响因子：
6.5
通讯作者：
Hu, Lizhi
中科院分区：
文献类型：
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作者：
Li, Yingxi;Wu, Jiangmei;Hu, Lizhi
转移是皮肤黑色素瘤患者死亡率高的主要原因，也是皮肤黑色素瘤治疗中的一个难题。因此，探讨皮肤转移性黑色素瘤的分子机制，开发新的治疗方法具有重要的临床价值。MED 1作为激活子依赖性转录所需的因子，据报道参与了癌症的发生和进展。在这项研究中，我们发现MED 1在皮肤黑色素瘤患者中高表达。MED 1下调可诱导细胞上皮向间质转化，促进体内外皮肤黑色素瘤的迁移、侵袭和转移。进一步的分析表明，在Med 1敲低的细胞中，TGF β/SMAD 2信号通路介导了上皮向间充质转化表型和迁移的增加。在用TGFb抑制剂治疗后观察到相反的结果。为了进一步探讨其机制，我们发现MED 1与SMAD 2相互作用，并且MED 1下调可以通过抑制SMAD 2泛素化来保护SMAD 2免受降解。总之，这些结果表明，在皮肤黑色素瘤的转移中，MED 1通过SMAD 2泛素化抑制TGF β信号通路以减少细胞上皮向间充质转化表型和迁移。我们的研究结果阐明了MED 1在皮肤黑色素瘤转移中的作用，并为皮肤黑色素瘤的治疗策略提供了靶点。
Metastasis is the main reason for the high mortality of patients and indeed a difficult task in the treatment of cutaneous melanoma. Therefore, it is of great clinical value to explore the molecular mechanism of cutaneous metastatic melanoma and develop novel therapies. MED1, acting as a factor required for activator-dependent transcription, is reported to be involved in carcinogenesis and progression. In this study, we found that MED1 was highly expressed in patients with cutaneous melanoma. MED1 downregulation could induce cellular epithelial-to-mesenchymal transition and promote migration, invasion, and metastasis of cutaneous melanoma in vivo and in vitro. Further analysis showed that in Med1 knockdown cells, the TGFb/SMAD2 signaling pathway mediated an increase in epithelial-to-mesenchymal transition phenotype and migration. The opposite results were observed after treatment with TGFb inhibitors. To further explore the mechanism, we found that MED1 interacted with SMAD2, and MED1 downregulation could protect SMAD2 from degradation by inhibiting SMAD2 ubiquitination. Together, these results suggest that MED1 inhibited TGFb signaling pathway to reduce cell epithelial-to-mesenchymal transition phenotype and migration through SMAD2 ubiquitination in the metastasis of cutaneous melanoma. Our findings elucidated the role of MED1 in the metastasis of cutaneous melanoma and provided a target for the therapeutic strategies of cutaneous melanoma.