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Amplification of SMYD3 promotes tumorigenicity and intrahepatic metastasis of hepatocellular carcinoma via upregulation of CDK2 and MMP2

Oncogene volume 38, pages 4948–4961 (2019)Cite this article

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Abstract

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.

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Acknowledgements

This study was supported by the grants including Natural Science Foundation of China (No. 30600156; 30970837; 81101135; 81102270; 81602701, 81760496), Natural Science Foundation of Guangdong Province (No. 2014A030313053; 2016A030313278; 2016A030313365; 2017A030313547), Science and Technology Projects Foundation of Guangdong Province (No. 2015A070710006; 2016A020215053), and Science and Technology Projects Foundation of Guangzhou City (No. 201507020037; 201607010260).

Author contributions

FL and HPL designed the research. YW, BHX, YHH, WHL, JYN, JH, WC, JZ, LS, and LFX performed the experiments and collected data. YW, BHX, YHH, and WHL finished statistical analysis. FL and HPL wrote the manuscript. All authors contributed to the writing and reviewing of the manuscript, and approved the final manuscript for submission.

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  1. These authors contributed equally: Yu Wang, Bin-hui Xie, Yong-hui Huang, Wei-hao Lin, Jia-yan Ni

Authors and Affiliations

  1. Department of Interventional Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, People’s Republic of China

    Yu Wang, Wei Cui & Long Shen

  2. Department of Hepatobiliary Surgery, The First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, People’s Republic of China

    Bin-hui Xie

  3. Department of Thyroid & Breast Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, People’s Republic of China

    Wei-hao Lin

  4. Department of Interventional Radiology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, People’s Republic of China

    Yong-hui Huang

  5. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Interventional Radiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People’s Republic of China

    Jia-yan Ni & Lin-feng Xu

  6. Department of Medical Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, People’s Republic of China

    Jie Hu & He-ping Li

  7. Department of Rheumatology and Clinical Immunology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, People’s Republic of China

    Jun Zhou & Fan Lian

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Wang, Y., Xie, Bh., Lin, Wh. et al. Amplification of SMYD3 promotes tumorigenicity and intrahepatic metastasis of hepatocellular carcinoma via upregulation of CDK2 and MMP2. Oncogene 38, 4948–4961 (2019). https://doi.org/10.1038/s41388-019-0766-x

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