Amplification of SMYD3 promotes tumorigenicity and intrahepatic metastasis of hepatocellular carcinoma via upregulation of CDK2 and MMP2
Amplification of SMYD3 promotes tumorigenicity and intrahepatic metastasis of hepatocellular carcinoma via upregulation of CDK2 and MMP2
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SMYD3扩增通过上调CDK2和MMP2促进肝细胞癌的致瘤性和肝内转移
DOI：
10.1038/s41388-019-0766-x
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发表时间：
2019-06-20
期刊：
影响因子：
8
通讯作者：
Li, He-ping
中科院分区：
文献类型：
--
作者：
Wang, Yu;Xie, Bin-hui;Li, He-ping
SMYD 3是SET和MYND结构域（SMYD）家族的成员，也已被证明作为组蛋白赖氨酸甲基转移酶在很大程度上参与基因转录调控和多种人类癌症的进展。然而，SMYD 3在肝细胞癌（HCC）的临床和进展中的作用和意义仍不清楚。在此，我们发现SMYD 3在肝硬化肝脏中增加，并且在肝细胞癌（HCC）组织和细胞系中显著上调。随后的分析表明，SMYD 3的高表达水平与HCC的恶性特征显著相关，并预测患者的预后不良。我们的研究结果表明，在体外和体内，SMYD 3的过表达增加，而SMYD 3的沉默抑制，细胞增殖，侵袭力和致瘤性。SMYD 3还促进HCC细胞的肝内转移。对于SMYD 3的作用机制，我们发现SMYD 3与CDK 2和MMP 2启动子结合，并在相应的启动子处增加H3 K4 me 3的修饰，从而促进基因转录。重要的是，用BCI-121抑制剂药理学靶向SMYD 3有效地抑制了HCC细胞的致瘤性。最后，我们的研究结果表明，基因位点扩增是肝癌中SMYD 3过表达的原因。这些发现不仅揭示了SMYD 3过表达通过上调CDK 2和MMP 2促进HCC细胞的致瘤性和肝内转移，而且提示SMYD 3可能是一种实用的预后标志物或治疗靶点。
SMYD3, a member that belongs to the SET and MYND-domain (SMYD) family, has also been proven to largely participate in gene transcription regulation and progression of several human cancers as a histone lysine methyltransferase. However, the role and significance of SMYD3 in both the clinic and progression of hepatocellular carcinoma (HCC) remain unclear. Herein, we find that SMYD3 is increased in cirrhotic livers, and strikingly upregulated in hepatocellular carcinoma (HCC) tissues and cell lines. Subsequent analyses suggest that high expression level of SMYD3 significantly correlates with the malignant characteristics of HCC, and predicts poor prognosis in patients. Our results show that overexpression of SMYD3 increases, while silencing of SMYD3 inhibits, cell proliferation, invasiveness and tumorigenicity both in vitro and in vivo. SMYD3 also promotes intrahepatic metastasis of HCC cells. For the mechanisms, we identify that SMYD3 bound to CDK2 and MMP2 promoter and increased H3K4me3 modification at the corresponding promoters to promote gene transcription. Importantly, pharmacological targeting of SMYD3 with BCI-121 inhibitor effectively repressed the tumorigenicity of HCC cells. Finally, our results show that gene locus amplification is a cause for SMYD3 overexpression in HCC. These findings not only uncover that SMYD3 overexpression promotes the tumorigenicity and intrahepatic metastasis of HCC cell via upregulation of CDK2 and MMP2, but also suggest SMYD3 could be a practical prognosis marker or therapeutic target against the disease.