2. Academic Validation
  3. DNMT1 determines osteosarcoma cell resistance to apoptosis by associatively modulating DNA and mRNA cytosine-5 methylation

DNMT1 determines osteosarcoma cell resistance to apoptosis by associatively modulating DNA and mRNA cytosine-5 methylation

  • FASEB J. 2023 Dec;37(12):e23284. doi: 10.1096/fj.202301306R.
Dongxing Shao 1 2,  Cihang Liu 1 2,  Yingying Wang 2,  Jing Lin 3,  Xiaolei Cheng 4,  Pei Han 1,  Zhen Li 2,  Dongdong Jian 1,  Junwei Nie 5,  Mingyang Jiang 5,  Yuanzhi Wei 5,  Junyue Xing 2 6,  Zhiping Guo 2 6,  Wengong Wang 1,  Xia Yi 1,  Hao Tang 2 6
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
  • 2 National Health Commission Key Laboratory of Cardiovascular Regenerative Medicine, Heart Center of Henan Provincial People's Hospital, Central China Fuwai Hospital of Zhengzhou University, Fuwai Central China Cardiovascular Hospital & Central China Branch of National Center for Cardiovascular Diseases, Zhengzhou, China.
  • 3 Department of Laboratory Medicine, the Fourth Medical Center, Chinese PLA General Hospital, Beijing, China.
  • 4 Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, China.
  • 5 R&D Department, Vazyme Biotech Co., Ltd, Nanjing, China.
  • 6 Henan Key Laboratory of Chronic Disease Management, Department of Health Management Center, Henan Provincial People's Hospital, Department of Health Management Center of Central China Fuwai Hospital, Central China Fuwai Hospital of Zhengzhou University, Zhengzhou, China.
PMID: 37905981 DOI: 10.1096/fj.202301306R
Abstract

Cellular Apoptosis is a central mechanism leveraged by chemotherapy to treat human cancers. 5-Methylcytosine (m5C) modifications installed on both DNA and mRNA are documented to regulate Apoptosis independently. However, the interplay or crosstalk between them in cellular Apoptosis has not yet been explored. Here, we reported that promoter methylation by DNMT1 coordinated with mRNA methylation by NSun2 to regulate osteosarcoma cell Apoptosis. DNMT1 was induced during osteosarcoma cell Apoptosis triggered by chemotherapeutic drugs, whereas NSun2 expression was suppressed. DNMT1 was found to repress NSun2 expression by methylating the NSun2 promoter. Moreover, DNMT1 and NSun2 regulate the anti-apoptotic genes AXL, NOTCH2, and YAP1 through DNA and mRNA methylation, respectively. Upon exposure to cisplatin or doxorubicin, DNMT1 elevation drastically reduced the expression of these anti-apoptotic genes via enhanced promoter methylation coupled with NSun2 ablation-mediated attenuation of mRNA methylation, thus rendering osteosarcoma cells to Apoptosis. Collectively, our findings establish crosstalk of importance between DNA and RNA cytosine methylations in determining osteosarcoma resistance to Apoptosis during chemotherapy, shedding new LIGHT on future treatment of osteosarcoma, and adding additional layers to the control of gene expression at different epigenetic levels.

Keywords

5-Methylcytosine; DNMT1; NSun2; apoptosis; osteosarcoma.

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