Targeting SLP2-mediated lipid metabolism reprograming restricts proliferation and metastasis of hepatocellular carcinoma and promotes sensitivity to Lenvatinib
Targeting SLP2-mediated lipid metabolism reprograming restricts proliferation and metastasis of hepatocellular carcinoma and promotes sensitivity to Lenvatinib
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靶向SLP2介导的脂代谢重编抑制肝细胞癌的增殖和转移并提高对Lenvatinib的敏感性
DOI：
10.1038/s41388-022-02551-z
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发表时间：
2022-12-06
期刊：
影响因子：
8
通讯作者：
Liu, Lianxin
中科院分区：
文献类型：
--
作者：
Liu, Yufeng;Sun, Linmao;Liu, Lianxin
SLP 2是一种位于线粒体上的蛋白质，已被证明与线粒体生物合成有关。在这里，我们探讨了SLP 2调节肝细胞癌发展的潜在机制。SLP 2可与JNK 2的C端结合，影响JNK 2的泛素化蛋白酶体降解途径，维持JNK 2蛋白的稳定性。JNK 2的增加显著增加SREBP 1活性，促进SREBP 1易位到细胞核中以促进从头脂肪生成。JNK 2 C-末端的改变使SLP 2不能介导SLP 2增强的从头脂肪生成。YTHDF 1以L3/m（6）A依赖的方式与SLP 2 mRNA相互作用。在自发性HCC动物模型中，SLP 2/c-Myc/sgP 53增加自发性HCC的发生率、肿瘤体积和肿瘤数量。重要的是，统计分析显示，SLP 2水平与肿瘤大小、肿瘤转移、总生存期和患者的无病生存期相关。靶向SLP 2/SREBP 1通路与乐伐替尼联合，可在体内有效抑制SLP 2高表达的HCC肿瘤的增殖和转移。这些结果说明了一个直接的脂肪生成促进作用的原癌SLP 2，提供了一个机制之间的联系从头脂肪生成和HCC。
SLP2, a protein located on mitochondrial, has been shown to be associated with mitochondrial biosynthesis. Here we explored the potential mechanisms by which SLP2 regulates the development of hepatocellular carcinoma. SLP2 could bind to the c-terminal of JNK2 to affect the ubiquitinated proteasomal degradation pathway of JNK2 and maintain the protein stability of JNK2. The increase of JNK2 markedly increases SREBP1 activity, promoting SREBP1 translocation into the nucleus to promote de novo lipogenesis. Alteration of the JNK2 C-terminal disables SLP2 from mediating SLP2-enhanced de novo lipogenesis. YTHDF1 interacts with SLP2 mRNA in a METTL3/m(6)A-dependent manner. In a spontaneous HCC animal model, SLP2/c-Myc/sgP53 increases the incidence rate of spontaneous HCC, tumor volume, and tumor number. Importantly, statistical analyses show that levels of SLP2 correlate with tumor sizes, tumor metastasis, overall survival, and disease-free survival of the patients. Targeting the SLP2/SREBP1 pathway effectively inhibits proliferation and metastasis of HCC tumors with high SLP2 expression in vivo combined with lenvatinib. These results illustrate a direct lipogenesis-promoting role of the pro-oncogenic SLP2, providing a mechanistic link between de novo lipogenesis and HCC.