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JMJD3通过不同机制促进弥漫性大B细胞淋巴瘤亚型的存活。

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

作者信息

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

机构信息

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.

出版信息

Oncotarget. 2016 May 17;7(20):29387-99. doi: 10.18632/oncotarget.8836.

DOI:10.18632/oncotarget.8836
PMID:27102442
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5045403/
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.

摘要

JMJD3（含Jumonji结构域蛋白3）是一种组蛋白H3赖氨酸27（H3K27）去甲基化酶，据报道其参与生发中心B细胞的抗原驱动分化。然而，对于JMJD3在弥漫性大B细胞淋巴瘤（DLBCL）进展中的作用机制仍知之甚少。在本研究中，我们调查了DLBCL中JMJD3依赖的亚型特异性生存效应。我们的数据表明，在ABC亚型中，JMJD3的沉默以去甲基化酶活性依赖的方式抑制干扰素调节因子4（IRF4）的表达。IRF4反过来刺激JMJD3的表达，形成一个促进这些细胞存活的正反馈环。因此，IRF4的表达足以挽救JMJD3抑制在ABC亚型而非GCB亚型中的促凋亡作用。相反，BCL-2的异位过表达完全抵消了JMJD3介导的GCB DLBCL细胞的存活。在体内，用针对JMJD3的siRNA处理可减小肿瘤体积，这与任一亚型中凋亡增加相一致。这表明它是一个共同靶点，尽管调节DCBCL存活的独特信号轴为治疗DLBCL亚型提供了不同的策略选择。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6eaf/5045403/3b60ed3a90cf/oncotarget-07-29387-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6eaf/5045403/e8bf087b651c/oncotarget-07-29387-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6eaf/5045403/a091b04b51d3/oncotarget-07-29387-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6eaf/5045403/215d02b8fd87/oncotarget-07-29387-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6eaf/5045403/615fd6d92b43/oncotarget-07-29387-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6eaf/5045403/879f06889ae9/oncotarget-07-29387-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6eaf/5045403/1754bb50e506/oncotarget-07-29387-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6eaf/5045403/3b60ed3a90cf/oncotarget-07-29387-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6eaf/5045403/e8bf087b651c/oncotarget-07-29387-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6eaf/5045403/a091b04b51d3/oncotarget-07-29387-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6eaf/5045403/215d02b8fd87/oncotarget-07-29387-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6eaf/5045403/615fd6d92b43/oncotarget-07-29387-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6eaf/5045403/879f06889ae9/oncotarget-07-29387-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6eaf/5045403/1754bb50e506/oncotarget-07-29387-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6eaf/5045403/3b60ed3a90cf/oncotarget-07-29387-g007.jpg

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