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  3. 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.
PMID: 34482361 DOI: 10.1038/s41392-021-00702-4
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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