Targeting cancer cell plasticity by HDAC inhibition to reverse EBV-induced dedifferentiation in nasopharyngeal carcinoma.
Jiajun XieZi-Feng WangWenjun FanYouping LiuFang LiuXiang-Bo WanMeiling LiuXuan WangDeshun ZengYan WangBin HeMin YanZijian ZhangMengjuan ZhangZhijie HouChunli WangZhijie KangWenfeng FangLi ZhangEric Wing-Fai LamXiang GuoJinsong YanYixin ZengMingyuan ChenQuentin LiuPublished in: Signal transduction and targeted therapy (2021)
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.
Keyphrases
- epstein barr virus
- diffuse large b cell lymphoma
- histone deacetylase
- poor prognosis
- high glucose
- dna methylation
- gene expression
- diabetic rats
- binding protein
- transcription factor
- papillary thyroid
- endothelial cells
- mesenchymal stem cells
- squamous cell carcinoma
- young adults
- protein protein
- amino acid
- replacement therapy