SMYD3 associates with the NuRD (MTA1/2) complex to regulate transcription and promote proliferation and invasiveness in hepatocellular carcinoma cells

BMC Biology

Research Article

Siyu Zhao¹  Liyun Zheng¹  Yajie Wang¹  Rongfang Qiu¹  Ziwei Xu¹  Minjiang Chen¹  Jiansong Ji¹  Yang Yang¹  Weiqian Chen¹  Zhongwei Zhao¹  Bufu Tang¹  Qiaoyou Weng¹  Gaofeng Shu¹  Lin Shen¹ 

[1] 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, 323000, Lishui, China;Department of Interventional Radiology, Clinical College of The Affiliated Central Hospital, Lishui University, 323000, Lishui, China;

关键词: SMYD3;    Hepatocellular carcinoma;    NuRD complex;    IGFBP4;    Metastasis;   

DOI  :  10.1186/s12915-022-01499-6

 received in 2022-03-16, accepted in 2022-12-07,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundSMYD3, 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.ResultsUsing 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.ConclusionsThese 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.

【 授权许可】

CC BY   
© The Author(s) 2022

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