Signal Transduction and Targeted Therapy (Sep 2021)

Targeting cancer cell plasticity by HDAC inhibition to reverse EBV-induced dedifferentiation in nasopharyngeal carcinoma

  • Jiajun Xie,
  • Zifeng Wang,
  • Wenjun Fan,
  • Youping Liu,
  • Fang Liu,
  • Xiangbo Wan,
  • Meiling Liu,
  • Xuan Wang,
  • Deshun Zeng,
  • Yan Wang,
  • Bin He,
  • Min Yan,
  • Zijian Zhang,
  • Mengjuan Zhang,
  • Zhijie Hou,
  • Chunli Wang,
  • Zhijie Kang,
  • Wenfeng Fang,
  • Li Zhang,
  • Eric W-F Lam,
  • Xiang Guo,
  • Jinsong Yan,
  • Yixin Zeng,
  • Mingyuan Chen,
  • Quentin Liu

DOI
https://doi.org/10.1038/s41392-021-00702-4
Journal volume & issue
Vol. 6, no. 1
pp. 1 – 17

Abstract

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Abstract Application of differentiation therapy targeting cellular plasticity for the treatment of solid malignancies has been lagging. Nasopharyngeal carcinoma (NPC) is a distinctive cancer with poor differentiation and high prevalence of Epstein-Barr virus (EBV) infection. Here, we show that the expression of EBV latent protein LMP1 induces dedifferentiated and stem-like status with high plasticity through the transcriptional inhibition of CEBPA. Mechanistically, LMP1 upregulates STAT5A and recruits HDAC1/2 to the CEBPA locus to reduce its histone acetylation. HDAC inhibition restored CEBPA expression, reversing cellular dedifferentiation and stem-like status in mouse xenograft models. These findings provide a novel mechanistic epigenetic-based insight into virus-induced cellular plasticity and propose a promising concept of differentiation therapy in solid tumor by using HDAC inhibitors to target cellular plasticity.