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

ABSTRACT 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.