JMJD3 promotes survival of diffuse large B-cell lymphoma subtypes via distinct mechanisms

// Yan Zhang 1, 7, * , Long Shen 2, * , Dwayne G. Stupack 3 , Nan Bai 1 , Jing Xun 2 , Guosheng Ren 4 , Jihong Han 5 , Luyuan Li 5 , Yunping Luo 6 , Rong Xiang 1 , Xiaoyue Tan 2 1 Department of Immunology, Medical School of Nankai University, Tianjin 300071, China 2 Department of Pathology, Medical School of Nankai University, Tianjin 300071, China 3 UCSD Moores Cancer Center, University of California, San Diego, La Jolla CA 92093, USA 4 Molecular Oncology and Epigenetics Laboratory, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China 5 The College of Life Sciences, Nankai University, Tianjin 300071, China 6 Department of Immunology, Beijing Union Medical School, Beijing, 100010, China 7 Central Laboratory, Logistics University of Chinese People’s Armed Police Force, Tianjin, 300162, China * Co-first authors, these authors contributed equally to this work Correspondence to: Rong Xiang, email: rxiang@nankai.edu.cn Xiaoyue Tan, email: xiaoyuetan@nankai.edu.cn Keywords: DLBCL, apoptosis, JMJD3, IRF4, Bcl-2 Received: November 02, 2015      Accepted: March 28, 2016      Published: April 19, 2016 ABSTRACT JMJD3 (Jumonji domain containing-3), a histone H3 Lys27 (H3K27) demethylase, has been reported to be involved in the antigen-driven differentiation of germinal center B-cells. However, insight into the mechanism of JMJD3 in DLBCL (Diffuse large B-cell lymphoma) progression remains poorly understood. In this study, we investigated the subtype-specific JMJD3-dependent survival effects in DLBCL. Our data showed that in the ABC subtype, silencing-down of JMJD3 inhibited interferon regulatory factor 4 (IRF4) expression in a demethylase activity-dependent fashion. IRF4 reciprocally stimulated expression of JMJD3, forming a positive feedback loop that promoted survival in these cells. Accordingly, IRF4 expression was sufficient to rescue the pro-apoptotic effect of JMJD3 suppression in the ABC, but not in the GCB subtype. In contrast, ectopic overexpression of BCL-2 completely offset JMJD3-mediated survival in the GCB DLBCL cells. In vivo , treatment with siRNA to JMJD3 reduced tumor volume concordant with increased apoptosis in either subtype. This suggests it is a common target, though the distinctive signaling axes regulating DCBCL survival offer different strategic options for treating DLBCL subtypes.