Open AccessJMJD3 promotes survival of diffuse large B-cell lymphoma subtypes via distinct mechanisms
Author(s) -
Yan Zhang,
Long Shen,
Dwayne G. Stupack,
Nan Bai,
Jing Xun,
Guosheng Ren,
Jihong Han,
Luyuan Li,
Yunping Luo,
Rong Xiang,
Xiaoyue Tan
Publication year - 2016
Publication title -
oncotarget
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.373
H-Index - 127
ISSN - 1949-2553
DOI - 10.18632/oncotarget.8836
Subject(s) - cancer research , demethylase , irf4 , ectopic expression , diffuse large b cell lymphoma , gene silencing , biology , lymphoma , histone , apoptosis , transcription factor , chromatin , interferon regulatory factors , cell culture , immunology , genetics , gene
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.