2. Academic Validation
  3. ZBTB7C m6A modification incurred by METTL3 aberration promotes osteosarcoma progression

ZBTB7C m6A modification incurred by METTL3 aberration promotes osteosarcoma progression

  • Transl Res. 2023 Apr 28;S1931-5244(23)00072-5. doi: 10.1016/j.trsl.2023.04.005.
Xueying An 1,  Wenshu Wu 1,  Lin Yang 2,  Jian Dong 3,  Bin Liu 3,  Junxia Guo 2,  Jianmei Chen 4,  Baosheng Guo 5,  Wangsen Cao 6,  Qing Jiang 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Pharmaceutical Biotechnology, Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
  • 2 Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, China.
  • 3 State Key Laboratory of Pharmaceutical Biotechnology, Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.; Branch of National Clinical Research Center for Orthopedics, Sports Medicine and Rehabilitation, Nanjing, China.
  • 4 Institute of Translational Medicine, Medical College,Yangzhou University, Yangzhou, China.. Electronic address: cjm@yzu.edu.cn.
  • 5 State Key Laboratory of Pharmaceutical Biotechnology, Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.; Branch of National Clinical Research Center for Orthopedics, Sports Medicine and Rehabilitation, Nanjing, China.. Electronic address: borisguo@nju.edu.cn.
  • 6 Nanjing University Medical School, Jiangsu Key Lab of Molecular Medicine. Nanjing, China.; Department of Central Laboratory, Yancheng First Hospital, Affiliated Hospital of Nanjing University Medical School, The First People's Hospital of Yancheng, Yancheng, China.. Electronic address: wangsencao@nju.edu.cn.
  • 7 State Key Laboratory of Pharmaceutical Biotechnology, Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.; Branch of National Clinical Research Center for Orthopedics, Sports Medicine and Rehabilitation, Nanjing, China.. Electronic address: qingj@nju.edu.cn.
PMID: 37121538 DOI: 10.1016/j.trsl.2023.04.005
Abstract

Aberrant N6-methyladenosine (m6A) modification of mRNAs contributes significantly to the epigenetic tumorigenesis, however, its precise role and the key targets in osteosarcoma (OS) are not defined. Here we reported that selective METTL3 (methyltransferase like 3) elevation and the consequential increase of m6A modification causally affect OS progression. The fast-growing OS cells displayed preferential upregulation of METTL3 and increased m6A modification. Conversely, m6A inhibition by 3-deazaadenosine, siRNA-mediated METTL3 knockdown or a METTL3-selective inhibitor by STM2457 effectively inhibits OS cell growth and induced OS cell Apoptosis. Further investigation revealed that an oncogenic protein ZBTB7C was likely a critical m6A target that mediated the oncogenic effects. ZBTB7C mRNA contains a typical m6A motif of high confidence and its mRNA and protein were enriched with increased m6A modification in OS samples/cells. In an OS xenograft model, STM2457 or siRNA-mediated METTL3 knockdown effectively lowed ZBTB7C abundance. More importantly, the anti-OS effects of STM2457 were significantly reduced when ZBTB7C was overexpressed by lentivirus. Together, our results demonstrate that the METTL3 aberration and the resultant ZBTB7C m6A modification form an important epigenetic regulatory loop that promotes OS progression, and targeting the METTL3/ZBTB7C axis may provide novel insights into the potential strategies for OS therapy.

Keywords

Apoptosis; METTL3; N6-methyladenosine; Osteosarcoma; ZBTB7C.

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