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.

Details

Title
Targeting cancer cell plasticity by HDAC inhibition to reverse EBV-induced dedifferentiation in nasopharyngeal carcinoma
Author
Xie Jiajun 1 ; Wang, Zifeng 2   VIAFID ORCID Logo  ; Fan Wenjun 3 ; Liu, Youping 2 ; Liu, Fang 2 ; Wan Xiangbo 4   VIAFID ORCID Logo  ; Liu, Meiling 2 ; Wang, Xuan 2 ; Zeng Deshun 2 ; Wang, Yan 3 ; He, Bin 2 ; Yan, Min 2 ; Zhang, Zijian 2 ; Zhang Mengjuan 3 ; Hou Zhijie 3 ; Wang, Chunli 3 ; Kang, Zhijie 3 ; Fang Wenfeng 2 ; Zhang, Li 2 ; Lam, Eric W-F 2   VIAFID ORCID Logo  ; Guo, Xiang 2 ; Yan, Jinsong 5 ; Zeng Yixin 2 ; Chen, Mingyuan 2 ; Liu, Quentin 6 

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 (GRID:grid.488530.2) (ISNI:0000 0004 1803 6191); Dalian Medical University, Institute of Cancer Stem Cell, Cancer Center, Dalian, China (GRID:grid.411971.b) (ISNI:0000 0000 9558 1426); The Affiliated Second Hospital of Dalian Medical University, 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, Dalian, China (GRID:grid.452828.1) 
2  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 (GRID:grid.488530.2) (ISNI:0000 0004 1803 6191) 
3  Dalian Medical University, Institute of Cancer Stem Cell, Cancer Center, Dalian, China (GRID:grid.411971.b) (ISNI:0000 0000 9558 1426) 
4  The Sixth Affiliated Hospital of Sun Yat-sen University, Department of Radiation Oncology, Guangzhou, China (GRID:grid.488525.6) 
5  The Affiliated Second Hospital of Dalian Medical University, 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, Dalian, China (GRID:grid.452828.1) 
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 (GRID:grid.488530.2) (ISNI:0000 0004 1803 6191); Dalian Medical University, Institute of Cancer Stem Cell, Cancer Center, Dalian, China (GRID:grid.411971.b) (ISNI:0000 0000 9558 1426); The Third Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen Institute of Hematology, Guangzhou, China (GRID:grid.412558.f) (ISNI:0000 0004 1762 1794) 
Publication year
2021
Publication date
2021
Publisher
Nature Publishing Group
ISSN
20959907
e-ISSN
20593635
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41392-021-00702-4
ProQuest document ID
2569112913
Copyright
© The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.