JMJD3 promotes survival of diffuse large B-cell lymphoma subtypes via distinct mechanisms
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Yan Zhang1,7,*, Long Shen2,*, Dwayne G. Stupack3, Nan Bai1, Jing Xun2, Guosheng Ren4, Jihong Han5, Luyuan Li5, Yunping Luo6, Rong Xiang1, Xiaoyue Tan2
1Department of Immunology, Medical School of Nankai University, Tianjin 300071, China
2Department of Pathology, Medical School of Nankai University, Tianjin 300071, China
3UCSD Moores Cancer Center, University of California, San Diego, La Jolla CA 92093, USA
4Molecular Oncology and Epigenetics Laboratory, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
5The College of Life Sciences, Nankai University, Tianjin 300071, China
6Department of Immunology, Beijing Union Medical School, Beijing, 100010, China
7Central Laboratory, Logistics University of Chinese People’s Armed Police Force, Tianjin, 300162, China
*Co-first authors, these authors contributed equally to this work
Rong Xiang, email: email@example.com
Xiaoyue Tan, email: firstname.lastname@example.org
Keywords: DLBCL, apoptosis, JMJD3, IRF4, Bcl-2
Received: November 02, 2015 Accepted: March 28, 2016 Published: April 19, 2016
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.
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