SMYD3 associates with the NuRD (MTA1/2) complex to regulate transcription and promote proliferation and invasiveness in hepatocellular carcinoma cells
Yang Yang,
Rongfang Qiu,
Siyu Zhao,
Lin Shen,
Bufu Tang,
Qiaoyou Weng,
Ziwei Xu,
Liyun Zheng,
Weiqian Chen,
Gaofeng Shu,
Yajie Wang,
Zhongwei Zhao,
Minjiang Chen,
Jiansong Ji
Affiliations
Yang Yang
Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Imaging Diagnosis and Interventional Minimally Invasive Institute, The Fifth Affiliated Hospital of Wenzhou Medical University
Rongfang Qiu
Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Imaging Diagnosis and Interventional Minimally Invasive Institute, The Fifth Affiliated Hospital of Wenzhou Medical University
Siyu Zhao
Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Imaging Diagnosis and Interventional Minimally Invasive Institute, The Fifth Affiliated Hospital of Wenzhou Medical University
Lin Shen
Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Imaging Diagnosis and Interventional Minimally Invasive Institute, The Fifth Affiliated Hospital of Wenzhou Medical University
Bufu Tang
Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Imaging Diagnosis and Interventional Minimally Invasive Institute, The Fifth Affiliated Hospital of Wenzhou Medical University
Qiaoyou Weng
Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Imaging Diagnosis and Interventional Minimally Invasive Institute, The Fifth Affiliated Hospital of Wenzhou Medical University
Ziwei Xu
Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Imaging Diagnosis and Interventional Minimally Invasive Institute, The Fifth Affiliated Hospital of Wenzhou Medical University
Liyun Zheng
Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Imaging Diagnosis and Interventional Minimally Invasive Institute, The Fifth Affiliated Hospital of Wenzhou Medical University
Weiqian Chen
Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Imaging Diagnosis and Interventional Minimally Invasive Institute, The Fifth Affiliated Hospital of Wenzhou Medical University
Gaofeng Shu
Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Imaging Diagnosis and Interventional Minimally Invasive Institute, The Fifth Affiliated Hospital of Wenzhou Medical University
Yajie Wang
Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Imaging Diagnosis and Interventional Minimally Invasive Institute, The Fifth Affiliated Hospital of Wenzhou Medical University
Zhongwei Zhao
Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Imaging Diagnosis and Interventional Minimally Invasive Institute, The Fifth Affiliated Hospital of Wenzhou Medical University
Minjiang Chen
Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Imaging Diagnosis and Interventional Minimally Invasive Institute, The Fifth Affiliated Hospital of Wenzhou Medical University
Jiansong Ji
Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Imaging Diagnosis and Interventional Minimally Invasive Institute, The Fifth Affiliated Hospital of Wenzhou Medical University
Abstract Background SMYD3, a member of the SET and MYND domain-containing (SMYD) family, is a histone methyltransferase (HMT) and transcription factor that plays an important role in transcriptional regulation in human carcinogenesis. Results Using affinity purification and mass spectrometry assays to identify SMYD3-associated proteins in hepatocellular carcinoma (HCC) cells, we found several previously undiscovered SMYD3-interacting proteins, including the NuRD (MTA1/2) complex, the METTL family, and the CRL4B complex. Transcriptomic analysis of the consequences of knocking down SMYD3, MTA1, or MTA2 in HCC cells showed that SMYD3/NuRD complex targets a cohort of genes, some of which are critically involved in cell growth and migration. qChIP analyses showed that SMYD3 knockdown led to a significant reduction in the binding of MTA1 or MTA2 to the promoters of IGFBP4 and led to a significant decrease in H4K20me3 and a marked increase in H4Ac at the IGFBP4 promoter. In addition, we demonstrated that SMYD3 promotes cell proliferation, invasion, and tumorigenesis in vivo and in vitro and found that its expression is markedly upregulated in human liver cancer. Knockdown of MTA1 or MTA2 had the same effect as knockdown of SMYD3 on proliferation and invasion of hepatocellular carcinoma cells. Catalytic mutant SMYD3 could not rescue the phenotypic effects caused by knockdown of SMYD3. Inhibitors of SMYD3 effectively inhibited the proliferation and invasiveness of HCC cells. Conclusions These findings revealed that SMYD3 could transcriptionally repress a cohort of target genes expression by associating with the NuRD (MTA1/2) complex, thereby promoting the proliferation and invasiveness of HCC cells. Our results support the case for pursuing SMYD3 as a practical prognostic marker or therapeutic target against HCC.
