Argininosuccinate Synthase 1-Deficiency Enhances the Cell Sensitivity to Arginine through Decreased DEPTOR Expression in Endometrial Cancer.
Argininosuccinate Synthase 1-Deficiency Enhances the Cell Sensitivity to Arginine through Decreased DEPTOR Expression in Endometrial Cancer.
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DOI：
10.1038/srep45504
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发表时间：
2017-03-30
影响因子：
4.6
通讯作者：
Morii E
中科院分区：
文献类型：
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作者：
Ohshima K;Nojima S;Tahara S;Kurashige M;Hori Y;Hagiwara K;Okuzaki D;Oki S;Wada N;Ikeda JI;Kanai Y;Morii E
精氨琥珀酸合成酶1（ASS 1）是精氨酸生物合成的限速酶。虽然ASS 1表达水平通常在几种肿瘤中降低，并且低ASS 1表达可能是预后不良的因素，但其潜在机制尚未阐明。在这项研究中，我们揭示了一种新的协会之间的ASS 1和迁移/侵袭子宫内膜肿瘤通过调节机械靶雷帕霉素复合物（mTORC）1信号。ASS 1基因敲除的细胞表现出增强的迁移和入侵响应精氨酸饥饿后精氨酸。在ASS 1基因敲除细胞中，DEPTOR，一种mTORC 1信号的抑制剂，被下调，mTORC 1信号在精氨酸的作用下被激活。ASS 1通过改变组蛋白甲基化在表观遗传学上增强DEPTOR表达。与这些发现相一致，类胶质瘤病例浸润前沿的肿瘤细胞显示出较低的ASS 1和DEPTOR表达。我们的研究结果表明，每个肿瘤细胞中的ASS 1水平与肿瘤微环境中精氨酸通过mTORC 1信号调节的侵袭能力相关。
Argininosuccinate synthetase 1 (ASS1) is a rate-limiting enzyme in arginine biosynthesis. Although ASS1 expression levels are often reduced in several tumors and low ASS1 expression can be a poor prognostic factor, the underlying mechanism has not been elucidated. In this study, we reveal a novel association between ASS1 and migration/invasion of endometrial tumors via regulation of mechanistic target of rapamycin complex (mTORC) 1 signaling. ASS1-knockout cells showed enhanced migration and invasion in response to arginine following arginine starvation. In ASS1-knockout cells, DEPTOR, an inhibitor of mTORC1 signal, was downregulated and mTORC1 signaling was more activated in response to arginine. ASS1 epigenetically enhanced DEPTOR expression by altering the histone methylation. Consistent with these findings, tumor cells at the invasive front of endometrioid carcinoma cases showed lower ASS1 and DEPTOR expression. Our findings suggest that ASS1 levels in each tumor cell are associated with invasion capability in response to arginine within the tumor microenvironment through mTORC1 signal regulation.