STAT5A modulates CDYL2/SLC7A6 pathway to inhibit the proliferation and invasion of hepatocellular carcinoma by targeting to mTORC1
STAT5A modulates CDYL2/SLC7A6 pathway to inhibit the proliferation and invasion of hepatocellular carcinoma by targeting to mTORC1
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DOI：
10.1038/s41388-022-02273-2
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发表时间：
2022-03-21
期刊：
影响因子：
8
通讯作者：
Li, Jinjun
中科院分区：
文献类型：
--
作者：
Chen, Xiaoxia;Wang, Zhenyu;Li, Jinjun
染色质结构域Y样2（CDYL2）作为已知参与精子发生的CDY家族成员，最近被报道参与乳腺癌的发生发展，但其在肝细胞癌（HCC）中的确切生物学作用仍不清楚。在这里，我们观察到 CDYL2 在人原发性 HCC 组织中下调，并且低水平的 CDYL2 表达与较差的生存率相关。功能获得和丧失实验表明CDYL2在体外和体内抑制HCC细胞的增殖和转移。从机制上讲，CDYL2 通过减少 SLC7A6 启动子区域上 H3K4me3 的富集来下调溶质载体家族 7 成员 6 (SLC7A6)。此外，我们还发现信号转导子和转录激活子5A（STAT5A）可以直接正向调节CDYL2的表达。因此，CDYL2受到STAT5A的调节，并通过下调SLC7A6来抑制氨基酸运输，进而抑制细胞生长的主调节因子mTORC1/S6K通路。一致地，HCC 中 CDYL2 表达与 STAT5A 和 SLC7A6 表达显着相关。总的来说，我们提出了一个 STAT5A/CDYL2/SLC7A6 轴模型，为 CDYL2 提供了新的见解，这可能作为预测 HCC 患者预后的潜在因素和治疗靶点。
Chromodomain Y-like 2 (CDYL2), as a member of CDY family known to be involved in spermatogenesis, has been reported to participate in breast cancer development recently, but its exact biological role in hepatocellular carcinoma (HCC) remains unclear. Here, we observed that CDYL2 was down-regulated in human primary HCC tissues and the low levels of CDYL2 expression were correlated with poor survival. Gain- and loss-of-function experiments showed that CDYL2 inhibited the proliferation and metastasis of HCC cells in vitro and in vivo. Mechanistically, CDYL2 down-regulates solute carrier family 7 member 6 (SLC7A6) by decreasing the enrichment of H3K4me3 on the promoter region of SLC7A6. Additionally, we also found that signal transducer and activator of transcription 5A (STAT5A) could directly and positively regulate the expression of CDYL2. Thus, CDYL2 was regulated by STAT5A, and suppressed the amino acid transportation through down-regulation of SLC7A6, and then inhibits the mTORC1/S6K pathway, a master regulator of cell growth. Consistently, CDYL2 expression correlated significantly with STAT5A and SLC7A6 expression in HCC. Collectively, we propose a model for a STAT5A/CDYL2/SLC7A6 axis that provides novel insight into CDYL2, which may serve as a potential factor for predicting prognosis and a therapeutic target for HCC patients.