2. Academic Validation
  3. Histone lysine methyltransferase SMYD3 promotes oral squamous cell carcinoma tumorigenesis via H3K4me3-mediated HMGA2 transcription

Histone lysine methyltransferase SMYD3 promotes oral squamous cell carcinoma tumorigenesis via H3K4me3-mediated HMGA2 transcription

  • Clin Epigenetics. 2023 May 26;15(1):92. doi: 10.1186/s13148-023-01506-9.
Zongcheng Yang 1,  Fen Liu 2,  Zongkai Li 1,  Nianping Liu 1,  Xinfeng Yao 1,  Yu Zhou 1,  Liyu Zhang 1,  Pan Jiang 1,  Honghong Liu 1,  Lingming Kong 3,  Chuandong Lang 4,  Xin Xu 5,  Jihui Jia 6,  Takahito Nakajima 7,  Wenchao Gu 8 9,  Lixin Zheng 10,  Zhihong Zhang 11
Affiliations

Affiliations

  • 1 Department of Stomatology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, People's Republic of China.
  • 2 Department of Clinical Laboratory, Linyi Central Hospital, Linyi, Shandong, People's Republic of China.
  • 3 Department of General Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, People's Republic of China.
  • 4 Department of Orthopedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, People's Republic of China.
  • 5 Department of Implantology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Shandong Key Laboratory of Oral Tissue Regeneration, Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, Shandong, People's Republic of China.
  • 6 Department of Microbiology/Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People's Republic of China.
  • 7 Department of Diagnostic and Interventional Radiology, University of Tsukuba, Tsukuba, Ibaraki, Japan.
  • 8 Department of Diagnostic and Interventional Radiology, University of Tsukuba, Tsukuba, Ibaraki, Japan. sunferrero@gmail.com.
  • 9 Department of Diagnostic Radiology and Nuclear Medicine, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan. sunferrero@gmail.com.
  • 10 Department of Microbiology/Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People's Republic of China. zhenglixin555@163.com.
  • 11 Department of Stomatology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, People's Republic of China. zhangzhihong769@163.com.
PMID: 37237385 DOI: 10.1186/s13148-023-01506-9
Abstract

Background: Epigenetic dysregulation is essential to the tumorigenesis of oral squamous cell carcinoma (OSCC). SET and MYND domain-containing protein 3 (SMYD3), a histone lysine methyltransferase, is implicated in gene transcription regulation and tumor development. However, the roles of SMYD3 in OSCC initiation are not fully understood. The present study investigated the biological functions and mechanisms involved in the SMYD3-mediated tumorigenesis of OSCC utilizing bioinformatic approaches and validation assays with the aim of informing the development of targeted therapies for OSCC.

Results: 429 chromatin regulators were screened by a machine learning approach and aberrant expression of SMYD3 was found to be closely associated with OSCC formation and poor prognosis. Data profiling of single-cell and tissue demonstrated that upregulated SMYD3 significantly correlated with aggressive clinicopathological features of OSCC. Alterations in copy number and DNA methylation patterns may contribute to SMYD3 overexpression. Functional experimental results suggested that SMYD3 enhanced Cancer cell stemness and proliferation in vitro and tumor growth in vivo. SMYD3 was observed to bind to the High Mobility Group AT-Hook 2 (HMGA2) promoter and elevated tri-methylation of histone H3 lysine 4 at the corresponding site was responsible for transactivating HMGA2. SMYD3 also was positively linked to HMGA2 expression in OSCC samples. Furthermore, treatment with the SMYD3 chemical inhibitor BCI-121 exerted anti-tumor effects.

Conclusions: Histone Methyltransferase activity and transcription-potentiating function of SMYD3 were found to be essential for tumorigenesis and the SMYD3-HMGA2 is a potential therapeutic target in OSCC.

Keywords

Epigenetics; HMGA2; Oral squamous cell carcinoma; SMYD3; Tumorigenesis.

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