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Epigenetic silencing of ZCCHC10 by the lncRNA SNHG1 promotes progression and venetoclax resistance of acute myeloid leukemia

  • Authors:
    • Hao Zhou
    • Qing Zhang
    • Wei Huang
    • Chunping He
    • Chang Zhou
    • Jianlin Zhou
    • Yichong Ning
  • View Affiliations / Copyright

    Affiliations: State Key Laboratory of Developmental Biology of Freshwater Fish & Key Laboratory of Protein Chemistry and Developmental Biology of the Ministry of Education, College of Life Science, Hunan Normal University, Changsha, Hunan 410081, P.R. China, Chongzuo Key Laboratory of Biomedical Clinical Transformation, The People's Hospital of Chongzuo, Youjiang Medical University for Nationalities, Chongzuo, Guangxi Zhuang Autonomous Region 532200, P.R. China
    Copyright: © Zhou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 64
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    Published online on: April 13, 2023
       https://doi.org/10.3892/ijo.2023.5512
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Abstract

The gene encoding the tumor suppressor p53 is the most frequently mutated gene in cancers. However, p53 mutation is rare in acute myeloid leukemia (AML), and p53 is inactivated predominantly by aberrant expression of p53 regulators (such as MDM2). A previous study by the authors revealed that the ZCCHC10 protein suppressed MDM2‑mediated degradation of the p53 protein in lung cancer. However, the expression and role of the ZCCHC10 gene in AML have not been investigated. In the present study, it was found that ZCCHC10 expression was downregulated in bone marrow samples of AML patients and that ZCCHC10 expression was significantly and negatively correlated with the expression of the lncRNA SNHG1. Suppression of SNHG1 decreased ZCCHC10 promoter methylation and increased ZCCHC10 expression. Notably, there is a putative binding motif in SNHG1 with full complementarity to five sites surrounding the CpG island in the ZCCHC10 promoter. Overexpression of wild‑type SNHG1 promoted ZCCHC10 methylation, but overexpression of SNHG1 with deletion of the binding motif did not. Further study identified that SNHG1 simultaneously bound to the ZCCHC10 promoter and the DNA methyltransferases DNMT1 and DNMT3B. These results indicated that SNHG1 recruits DNMT1 and DNMT3B to the ZCCHC10 promoter, resulting in hypermethylation of the ZCCHC10 promoter. Kaplan‑Meier survival analysis showed that ZCCHC10 expression was positively associated with overall survival in AML patients. In vitro experiments demonstrated that ZCCHC10 increased p53 expression and suppressed AML cell proliferation and survival. In the xenograft mouse model, ZCCHC10 decreased the proliferation of leukemic cells, improved the survival of leukemic mice, and increased sensitivity to the BCL inhibitor venetoclax. In conclusion, ZCCHC10 expression is suppressed by SNHG1‑induced DNA methylation in AML. Downregulation of ZCCHC10 decreases p53 activation, promotes cell proliferation and survival, and thereby accelerates AML progression and the acquisition of venetoclax resistance. The present study identified a SNHG1/ZCCHC10/p53 signaling axis in AML that may be a therapeutic target in this malignancy.
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Copy and paste a formatted citation
Spandidos Publications style
Zhou H, Zhang Q, Huang W, He C, Zhou C, Zhou J and Ning Y: Epigenetic silencing of ZCCHC10 by the lncRNA SNHG1 promotes progression and venetoclax resistance of acute myeloid leukemia. Int J Oncol 62: 64, 2023.
APA
Zhou, H., Zhang, Q., Huang, W., He, C., Zhou, C., Zhou, J., & Ning, Y. (2023). Epigenetic silencing of ZCCHC10 by the lncRNA SNHG1 promotes progression and venetoclax resistance of acute myeloid leukemia. International Journal of Oncology, 62, 64. https://doi.org/10.3892/ijo.2023.5512
MLA
Zhou, H., Zhang, Q., Huang, W., He, C., Zhou, C., Zhou, J., Ning, Y."Epigenetic silencing of ZCCHC10 by the lncRNA SNHG1 promotes progression and venetoclax resistance of acute myeloid leukemia". International Journal of Oncology 62.5 (2023): 64.
Chicago
Zhou, H., Zhang, Q., Huang, W., He, C., Zhou, C., Zhou, J., Ning, Y."Epigenetic silencing of ZCCHC10 by the lncRNA SNHG1 promotes progression and venetoclax resistance of acute myeloid leukemia". International Journal of Oncology 62, no. 5 (2023): 64. https://doi.org/10.3892/ijo.2023.5512
Copy and paste a formatted citation
x
Spandidos Publications style
Zhou H, Zhang Q, Huang W, He C, Zhou C, Zhou J and Ning Y: Epigenetic silencing of ZCCHC10 by the lncRNA SNHG1 promotes progression and venetoclax resistance of acute myeloid leukemia. Int J Oncol 62: 64, 2023.
APA
Zhou, H., Zhang, Q., Huang, W., He, C., Zhou, C., Zhou, J., & Ning, Y. (2023). Epigenetic silencing of ZCCHC10 by the lncRNA SNHG1 promotes progression and venetoclax resistance of acute myeloid leukemia. International Journal of Oncology, 62, 64. https://doi.org/10.3892/ijo.2023.5512
MLA
Zhou, H., Zhang, Q., Huang, W., He, C., Zhou, C., Zhou, J., Ning, Y."Epigenetic silencing of ZCCHC10 by the lncRNA SNHG1 promotes progression and venetoclax resistance of acute myeloid leukemia". International Journal of Oncology 62.5 (2023): 64.
Chicago
Zhou, H., Zhang, Q., Huang, W., He, C., Zhou, C., Zhou, J., Ning, Y."Epigenetic silencing of ZCCHC10 by the lncRNA SNHG1 promotes progression and venetoclax resistance of acute myeloid leukemia". International Journal of Oncology 62, no. 5 (2023): 64. https://doi.org/10.3892/ijo.2023.5512
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