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Article Open Access

LMP1 mediates tumorigenesis through persistent epigenetic modifications and PGC1β upregulation

  • Authors:
    • Siliang Chen
    • Ping Zhang
    • Jia Feng
    • Rui Li
    • Junhui Chen
    • Wei V. Zheng
    • Hongyu Zhang
    • Paul Yao
  • View Affiliations / Copyright

    Affiliations: Department of Hematology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China, Intervention and Cell Therapy Center, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
    Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 53
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    Published online on: February 2, 2023
       https://doi.org/10.3892/or.2023.8490
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Abstract

Latent membrane protein 1 (LMP1), which is encoded by the Epstein‑Barr virus (EBV), has been considered as an oncogene, although the detailed mechanism behind its function remains unclear. It has been previously reported that LMP1 promotes tumorigenesis by upregulation of peroxisome proliferator‑activated receptor‑γ coactivator‑1β (PGC1β). The present study aimed to investigate the potential mechanism for transient EBV/LMP1 exposure‑mediated persistent PGC1β expression and subsequent tumorigenesis through modification of mitochondrial function. Luciferase reporter assay, chromatin immunoprecipitation and DNA mutation techniques were used to evaluate the PGC1β‑mediated expression of dynamin‑related protein 1 (DRP1). Tumorigenesis was evaluated by gene expression, oxidative stress, mitochondrial function and in vitro cellular proliferation assays. The potential effects of EBV, LMP1 and PGC1β on tumor growth were evaluated in an in vivo xenograft mouse model. The present in vitro experiments showed that LMP1 knockdown did not affect PGC1β expression or subsequent cell proliferation in EBV‑positive tumor cells. PGC1β regulated DRP1 expression by coactivation of GA‑binding protein α and nuclear respiratory factor 1 located on the DRP1 promoter, subsequently modulating mitochondrial fission. Transient exposure of either EBV or LMP1 in human hematopoietic stem cells caused persistent epigenetic changes and PGC1β upregulation after long‑term cell culture even in the absence of EBV/LMP1, which decreased oxidative stress, and potentiated mitochondrial function and cell proliferation in vitro. Enhanced tumor growth and shortened survival were subsequently observed in vivo. It was concluded that PGC1β expression and subsequent cell proliferation were independent from LMP1 in EBV‑positive tumor cells. PGC1β modulated mitochondria fission by regulation of DRP1 expression. Transient EBV/LMP1 exposure caused persistent PGC1β expression, triggering tumor growth in the absence of LMP1. The present study proposes a novel mechanism for transient EBV/LMP1 exposure‑mediated tumorigenesis through persistent epigenetic changes and PGC1β upregulation, uncovering the reason why numerous forms of lymphoma exhibit upregulated PGC1β expression, but are devoid of EBV/LMP1.
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Copy and paste a formatted citation
Spandidos Publications style
Chen S, Zhang P, Feng J, Li R, Chen J, Zheng WV, Zhang H and Yao P: LMP1 mediates tumorigenesis through persistent epigenetic modifications and PGC1β upregulation. Oncol Rep 49: 53, 2023.
APA
Chen, S., Zhang, P., Feng, J., Li, R., Chen, J., Zheng, W.V. ... Yao, P. (2023). LMP1 mediates tumorigenesis through persistent epigenetic modifications and PGC1β upregulation. Oncology Reports, 49, 53. https://doi.org/10.3892/or.2023.8490
MLA
Chen, S., Zhang, P., Feng, J., Li, R., Chen, J., Zheng, W. V., Zhang, H., Yao, P."LMP1 mediates tumorigenesis through persistent epigenetic modifications and PGC1β upregulation". Oncology Reports 49.3 (2023): 53.
Chicago
Chen, S., Zhang, P., Feng, J., Li, R., Chen, J., Zheng, W. V., Zhang, H., Yao, P."LMP1 mediates tumorigenesis through persistent epigenetic modifications and PGC1β upregulation". Oncology Reports 49, no. 3 (2023): 53. https://doi.org/10.3892/or.2023.8490
Copy and paste a formatted citation
x
Spandidos Publications style
Chen S, Zhang P, Feng J, Li R, Chen J, Zheng WV, Zhang H and Yao P: LMP1 mediates tumorigenesis through persistent epigenetic modifications and PGC1β upregulation. Oncol Rep 49: 53, 2023.
APA
Chen, S., Zhang, P., Feng, J., Li, R., Chen, J., Zheng, W.V. ... Yao, P. (2023). LMP1 mediates tumorigenesis through persistent epigenetic modifications and PGC1β upregulation. Oncology Reports, 49, 53. https://doi.org/10.3892/or.2023.8490
MLA
Chen, S., Zhang, P., Feng, J., Li, R., Chen, J., Zheng, W. V., Zhang, H., Yao, P."LMP1 mediates tumorigenesis through persistent epigenetic modifications and PGC1β upregulation". Oncology Reports 49.3 (2023): 53.
Chicago
Chen, S., Zhang, P., Feng, J., Li, R., Chen, J., Zheng, W. V., Zhang, H., Yao, P."LMP1 mediates tumorigenesis through persistent epigenetic modifications and PGC1β upregulation". Oncology Reports 49, no. 3 (2023): 53. https://doi.org/10.3892/or.2023.8490
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