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

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.

SUBMITTER: Xie J

PROVIDER: S-EPMC8418605 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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

Xie Jiajun J Wang Zifeng Z Fan Wenjun W Liu Youping Y Liu Fang F Wan Xiangbo X Liu Meiling M Wang Xuan X Zeng Deshun D Wang Yan Y He Bin B Yan Min M Zhang Zijian Z Zhang Mengjuan M Hou Zhijie Z Wang Chunli C Kang Zhijie Z Fang Wenfeng W Zhang Li L Lam Eric W-F EW Guo Xiang X Yan Jinsong J Zeng Yixin Y Chen Mingyuan M Liu Quentin Q

Signal transduction and targeted therapy 20210904 1

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 HD ...[more]

PMID: 34482361

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Project description:Non-keratinizing nasopharyngeal carcinoma, the major subtype of nasopharyngeal carcinoma, is characterized by low differentiation and a close relation to Epstein-Barr virus infection, which indicates a link between Epstein-Barr virus oncogenesis and loss of differentiation, and raises our interest in investigating the involvement of Epstein-Barr virus in nasopharyngeal carcinoma dedifferentiation. Our previous study showed abundant expression of an Epstein-Barr virus-encoded microRNA, BART10-3p, in nasopharyngeal carcinoma tissues, but the association between BART10-3p and nasopharyngeal carcinoma differentiation remains unknown. Here, we examined the expression and prognostic value of BART10-3p, and undertook bioinformatics analysis and functional assays to investigate the influence of BART10-3p on nasopharyngeal carcinoma differentiation and proliferation and the underpinning mechanism. Microarray analysis identified BART10-3p as the most significantly upregulated Epstein-Barr virus-encoded microRNA in nasopharyngeal carcinoma tissues and the upregulation was confirmed in two public datasets. The expression of BART10-3p was an independent unfavorable prognosticator in nasopharyngeal carcinoma and its integration with the clinical stage showed improved prognosis predictive performance. Bioinformatics analysis suggested a potential role of BART10-3p in tumor differentiation and progression. Functional assays demonstrated that BART10-3p could promote nasopharyngeal carcinoma cell dedifferentiation, epithelial-mesenchymal transition, and proliferation in vitro, and tumorigenicity in vivo. Mechanistically, BART10-3p directly targeted the 3'UTR of ALK7 and suppressed its expression. Reconstitution of ALK7 rescued BART10-3p-induced malignant phenotypes. Overall, our study demonstrates that BART10-3p promotes dedifferentiation and proliferation of nasopharyngeal carcinoma by targeting ALK7, suggesting a promising therapeutic opportunity to reverse the malignant phenotypes of nasopharyngeal carcinoma.

Dataset Information

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

Publications

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

Similar Datasets

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