1. Academic Validation
  2. Targeting cancer cell plasticity by HDAC inhibition to reverse EBV-induced dedifferentiation in nasopharyngeal carcinoma

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

  • Signal Transduct Target Ther. 2021 Sep 4;6(1):333. doi: 10.1038/s41392-021-00702-4.
Jiajun Xie  # 1 2 3 Zifeng Wang  # 1 Wenjun Fan  # 2 Youping Liu  # 1 Fang Liu  # 1 Xiangbo Wan  # 4 Meiling Liu 1 Xuan Wang 1 Deshun Zeng 1 Yan Wang 2 Bin He 1 Min Yan 1 Zijian Zhang 1 Mengjuan Zhang 2 Zhijie Hou 2 Chunli Wang 2 Zhijie Kang 2 Wenfeng Fang 1 Li Zhang 1 Eric W-F Lam 1 Xiang Guo 1 Jinsong Yan 5 Yixin Zeng 6 Mingyuan Chen 7 Quentin Liu 8 9 10
Affiliations

Affiliations

  • 1 Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China.
  • 2 Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, China.
  • 3 Department of Hematology; Liaoning Key Laboratory of Hematopoietic Stem Cell Transplantation and Translational Medicine; Liaoning Medical Center for Hematopoietic Stem Cell Transplantation; Dalian Key Laboratory of Hematology; Diamond Bay Institute of Hematology, The Affiliated Second Hospital of Dalian Medical University, Dalian, China.
  • 4 Department of Radiation Oncology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  • 5 Department of Hematology; Liaoning Key Laboratory of Hematopoietic Stem Cell Transplantation and Translational Medicine; Liaoning Medical Center for Hematopoietic Stem Cell Transplantation; Dalian Key Laboratory of Hematology; Diamond Bay Institute of Hematology, The Affiliated Second Hospital of Dalian Medical University, Dalian, China. yanjsdmu@126.com.
  • 6 Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China. zengyx@sysucc.org.cn.
  • 7 Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China. chenmy@sysucc.org.cn.
  • 8 Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China. liuq9@mail.sysu.edu.cn.
  • 9 Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, China. liuq9@mail.sysu.edu.cn.
  • 10 Sun Yat-sen Institute of Hematology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. liuq9@mail.sysu.edu.cn.
  • # Contributed equally.
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.

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