当前位置:科学网首页 > 小柯机器人 >详情
研究发现SIRT3的非癌基因依赖对淋巴瘤发生起到关键作用
作者:小柯机器人 发布时间:2019/7/8 14:00:43

美国康奈尔医学院Ari M. Melnick和Hening Lin研究组合作发现,对SIRT3的非癌基因依赖在淋巴瘤发生中起到关键作用。相关论文于2019年6月发表在国际学术期刊《Cancer Cell》杂志上。

弥漫性大B细胞淋巴瘤(DLBCL)起源于生发中心的B细胞,是具有遗传异质性与高增殖性的肿瘤。

研究人员发现,不管是何种亚型与遗传背景,DLBCL均依赖于线粒体赖氨酸去乙酰化酶SIRT3进行增殖、存活、自我更新以及体内生长。在VavP-Bcl2小鼠模型中敲除SIRT3能够降低B细胞淋巴癌的发生而不影响正常的生发中心形成。从机理上讲,SIRT3敲除通过影响依赖谷氨酸脱氢酶的谷氨酰胺到三羧酸(TCA)循环代谢途径,并降低乙酰辅酶A代谢池,从而引起自噬与细胞死亡。研究人员进一步开发了一个SIRT3的抑制剂——YC8-02,这个抑制剂能够表型模拟SIRT3的敲除并杀死DLBCL细胞。因此,这项工作建立了SIRT3作为非癌基因依赖的DLBCL代谢治疗靶点。

附:英文原文


Title: Non-oncogene Addiction to SIRT3 Plays a Critical Role in Lymphomagenesis

Author: Meng Li, Ying-Ling Chiang, Costas A. Lyssiotis, Michael R. Green, Hening Lin, Ari M. Melnick

Issue&Volume: Jun 10, 2019 Volume 35Issue 6

Abstract: Diffuse large B cell lymphomas (DLBCLs) are genetically heterogeneous and highly proliferative neoplasms derived from germinal center (GC) B cells. Here, we show that DLBCLs are dependent on mitochondrial lysine deacetylase SIRT3 for proliferation, survival, self-renewal, and tumor growth in vivo regardless of disease subtype and genetics. SIRT3 knockout attenuated B cell lymphomagenesis in VavP-Bcl2 mice without affecting normal GC formation. Mechanistically, SIRT3 depletion impaired glutamine flux to the TCA cycle via glutamate dehydrogenase and reduction in acetyl-CoA pools, which in turn induce autophagy and cell death. We developed a mitochondrial-targeted class I sirtuin inhibitor, YC8-02, which phenocopied the effects of SIRT3 depletion and killed DLBCL cells. SIRT3 is thus a metabolic non-oncogene addiction and therapeutic target for DLBCLs.

DOI: https://doi.org/10.1016/j.ccell.2019.05.002

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(19)30240-5

期刊信息

Cancer Cell:《癌细胞》,创刊于2002年。隶属于细胞出版社,最新IF:23.916
官方网址:https://www.cell.com/cancer-cell/home
投稿链接:https://www.editorialmanager.com/cancer-cell/default.aspx