JMJD3 promotes survival of diffuse large B-cell lymphoma subtypes via distinct mechanisms.
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.
Department of Immunology, Medical School of Nankai University, Tianjin 300071, China.|Central Laboratory, Logistics University of Chinese People's Armed Police Force, Tianjin, 300162, China.
Yan
Y
Zhang
Department of Pathology, Medical School of Nankai University, Tianjin 300071, China.
Long
L
Shen
UCSD Moores Cancer Center, University of California, San Diego, La Jolla CA 92093, USA.
Dwayne G
DG
Stupack
Department of Immunology, Medical School of Nankai University, Tianjin 300071, China.
Nan
N
Bai
Department of Pathology, Medical School of Nankai University, Tianjin 300071, China.
Jing
J
Xun
Molecular Oncology and Epigenetics Laboratory, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
Guosheng
G
Ren
The College of Life Sciences, Nankai University, Tianjin 300071, China.
Jihong
J
Han
The College of Life Sciences, Nankai University, Tianjin 300071, China.
Luyuan
L
Li
Department of Immunology, Beijing Union Medical School, Beijing, 100010, China.
Yunping
Y
Luo
Department of Immunology, Medical School of Nankai University, Tianjin 300071, China.
Rong
R
Xiang
Department of Pathology, Medical School of Nankai University, Tianjin 300071, China.
Xiaoyue
X
Tan
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D064593:Heterografts; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014407:Tumor Cells, Cultured
D056484:Jumonji Domain-Containing Histone Demethylases; C524220:KDM6B protein, human
Bcl-2; DLBCL; IRF4; JMJD3; apoptosis