Snail enhances arginine synthesis by inhibiting ubiquitination-mediated degradation of ASS1
Snail enhances arginine synthesis by inhibiting ubiquitination-mediated degradation of ASS1
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DOI：
10.15252/embr.202051780
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发表时间：
2021-06-29
期刊：
影响因子：
7.7
通讯作者：
Hou, Zhaoyuan
中科院分区：
文献类型：
--
作者：
Jia, Hao;Yang, Yuquan;Hou, Zhaoyuan
蜗牛是一种专门的转录抑制因子，是EMT和转移的主要诱导剂，但蜗牛引发的潜在信号级联反应仍不清楚。在这里，我们报道了Snail通过阻止非编码RNA loc113230介导的精氨酸琥珀酸合成酶1 （ASS1）的降解来促进结直肠癌（CRC）的迁移。LOC113230是一种新的Snail靶基因，在tgf - β诱导下，Snail与其近端启动子内的功能性e -box结合，抑制其表达。在异种移植实验中，LOC113230的异位表达能有效抑制结直肠癌细胞的生长、迁移和肺转移。从机制上讲，LOC113230作为支架促进LRPPRC和TRAF2 E3泛素连接酶募集到ASS1，导致ASS1泛素化和降解增强，精氨酸合成减少。此外，ASS1表达的升高对结直肠癌的生长和迁移至关重要。总之，这些发现表明，tgf - β和Snail通过抑制loc113230介导的LRPPRC/TRAF2/ASS1复合体组装来促进精氨酸合成，该复合体可以作为开发治疗结直肠癌的新治疗方法的潜在靶点。
Snail is a dedicated transcriptional repressor and acts as a master inducer of EMT and metastasis, yet the underlying signaling cascades triggered by Snail still remain elusive. Here, we report that Snail promotes colorectal cancer (CRC) migration by preventing non-coding RNA LOC113230-mediated degradation of argininosuccinate synthase 1 (ASS1). LOC113230 is a novel Snail target gene, and Snail binds to the functional E-boxes within its proximal promoter to repress its expression in response to TGF-beta induction. Ectopic expression of LOC113230 potently suppresses CRC cell growth, migration, and lung metastasis in xenograft experiments. Mechanistically, LOC113230 acts as a scaffold to facilitate recruiting LRPPRC and the TRAF2 E3 ubiquitin ligase to ASS1, resulting in enhanced ubiquitination and degradation of ASS1 and decreased arginine synthesis. Moreover, elevated ASS1 expression is essential for CRC growth and migration. Collectively, these findings suggest that TGF-beta and Snail promote arginine synthesis via inhibiting LOC113230-mediated LRPPRC/TRAF2/ASS1 complex assembly and this complex can serve as potential target for the development of new therapeutic approaches to treat CRC.