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:10.1038/s41392-021-00702-4

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.

Authors

Jiajun Xie^#^{1

2

3}, Zifeng Wang^#¹, Wenjun Fan^#², Youping Liu^#¹, Fang Liu^#¹, Xiangbo Wan^#⁴, Meiling Liu¹, Xuan Wang¹, Deshun Zeng¹, Yan Wang², Bin He¹, Min Yan¹, Zijian Zhang¹, Mengjuan Zhang², Zhijie Hou², Chunli Wang², Zhijie Kang², Wenfeng Fang¹, Li Zhang¹, Eric W-F Lam¹, Xiang Guo¹, Jinsong Yan⁵, Yixin Zeng⁶, Mingyuan Chen⁷, Quentin Liu^{8

9

10}

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. [email protected].
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. [email protected].
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. [email protected].
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. [email protected].
⁹ Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, China. [email protected].
¹⁰ Sun Yat-sen Institute of Hematology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. [email protected].

^# 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
CCAAT-Enhancer-Binding Proteins / genetics*
Cell Dedifferentiation / drug effects
Cell Line, Tumor
Cell Plasticity / drug effects
Epstein-Barr Virus Infections / drug therapy
Epstein-Barr Virus Infections / genetics
Epstein-Barr Virus Infections / pathology
Epstein-Barr Virus Infections / virology
Gene Expression Regulation, Neoplastic / drug effects
Gene Expression Regulation, Viral / drug effects
Herpesvirus 4, Human / drug effects
Herpesvirus 4, Human / pathogenicity
Heterografts
Histone Deacetylase Inhibitors / pharmacology*
Humans
Mice
Nasopharyngeal Carcinoma / drug therapy*
Nasopharyngeal Carcinoma / genetics
Nasopharyngeal Carcinoma / pathology
Nasopharyngeal Carcinoma / virology
STAT5 Transcription Factor / genetics*
Viral Matrix Proteins / genetics*

Substances

CCAAT-Enhancer-Binding Proteins
CEBPA protein, human
EBV-associated membrane antigen, Epstein-Barr virus
Histone Deacetylase Inhibitors
STAT5 Transcription Factor
Viral Matrix Proteins