EZH2 Activates HTLV-1 bZIP Factor-Mediated TGF-β Signaling in Adult T-Cell Leukemia.

Autor: Zhang X; Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, China.; College of Life Sciences, Zhejiang Normal University, Jinhua, China., Yi K; College of Life Sciences, Zhejiang Normal University, Jinhua, China., Wang B; College of Life Sciences, Zhejiang Normal University, Jinhua, China., Chu K; Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, China.; College of Life Sciences, Zhejiang Normal University, Jinhua, China., Liu J; College of Life Sciences, Zhejiang Normal University, Jinhua, China., Zhang J; Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, China., Fang J; Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, China., Zhao T; Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, China.; College of Life Sciences, Zhejiang Normal University, Jinhua, China.
Jazyk: angličtina
Zdroj: Journal of medical virology [J Med Virol] 2024 Nov; Vol. 96 (11), pp. e70025.
DOI: 10.1002/jmv.70025
Abstrakt: Adult T-cell leukemia (ATL) is an aggressive malignancy caused by human T-cell leukemia virus type 1 (HTLV-1) infection. Enhancer of zeste homolog 2 (EZH2) has been implicated in the development and progression of multiple cancers, including virus-induced malignancies. However, the potential function of EZH2 in HTLV-1-induced oncogenesis has not been clearly elucidated. In the present study, we showed that EZH2 was overexpressed and activated in HTLV-1-infected cell lines, potentially due to the activation of EZH2 promoter by HTLV-1 Tax and NF-κB p65 subunit. In addition, we found that EZH2 enhanced the HBZ-induced activation of TGF-β signaling in a histone methyltransferase-independent manner. As a mechanism for these actions, we found that EZH2 targeted Smad3/Smad4 to form a ternary complex, and the association between Smad3 and Smad4 was markedly enhanced in the presence of EZH2. Knockdown of EZH2 in ATL cells indeed repressed the expressions of the TGF-β target genes. In particular, EZH2 synergistically enhanced the HBZ/TGF-β-induced Foxp3 expression. Treatment of 3-Deazaneplanocin A, a specific inhibitor of EZH2 significantly inhibited the Foxp3 expression. Taken together, our results suggest that EZH2 may be involved in the differentiation of regulatory T cells through activating the HBZ-Smad3-TGF-β signaling axis, which is considered to be a key strategy for viral persistence.
(© 2024 Wiley Periodicals LLC.)
Databáze: MEDLINE
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