Research Papers:

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

Yan Zhang, Long Shen, Dwayne G. Stupack, Nan Bai, Jing Xun, Guosheng Ren, Jihong Han, Luyuan Li, Yunping Luo, Rong Xiang and Xiaoyue Tan _

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Oncotarget. 2016; 7:29387-29399. https://doi.org/10.18632/oncotarget.8836

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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

Correspondence to:

Rong Xiang, email: [email protected]

Xiaoyue Tan, email: [email protected]

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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