Fu Tingxiong, Lv Xiuwei, Kong Qingzhi, Yuan Changjing
Department of Pharmacy, The Central Hospital of Wuhan, Tongji Medical School, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Department of Oncology of Integrated Traditional Chinese and Western Medicine, The Central Hospital of Wuhan, Tongji Medical School, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Oncotarget. 2017 Jul 4;8(33):54809-54820. doi: 10.18632/oncotarget.18957. eCollection 2017 Aug 15.
SHARPIN (Shank-associated RH domain interacting protein) is the main component of the linear ubiquitin chain activation complex (LUBAC). SHARPIN is involved in regulating inflammation and cancer progression. However, whether SHARPIN plays an important role in lung cancer metastasis and the potential underlying mechanism are still unknown. Here, for the first time, we reported that SHARPIN expression is closely related to lung cancer progression. Moreover, SHARPIN plays a central role in controlling lung cancer cell metastasis. Mechanistic studies further revealed that PRMT5 (Protein arginine methyltransferase 5), responsible for catalyzing arginine methylation on histones, is a novel cofactor of SHARPIN. This finding provides the basis for further study of the crosstalk between protein ubiquitination and histone methylation. We further found that SHARPIN-PRMT5 is essential for the monomethylation of histones of chromatins at key metastasis-related genes, defining a new mechanism regulating cancer invasion. A novel MLL complex (ASH2 and WDR5) was implied in the link between histone arginine2 monomethylation (H3R2me1) and histone lysine4 trimethylation (H3K4me3) for the activation of metastasis-related genes. These novel findings establish a new epigenetic paradigm in which SHARPIN-PRMT5 has distinct roles in orchestrating chromatin environments for cancer-related genes via integrating signaling between H3R2me1 and H3K4me3.
SHARPIN（与ankyrin重复序列结构域相互作用的蛋白）是线性泛素链组装复合体（LUBAC）的主要成分。SHARPIN参与调节炎症和癌症进展。然而，SHARPIN在肺癌转移中是否发挥重要作用及其潜在的机制仍不清楚。在此，我们首次报道SHARPIN的表达与肺癌进展密切相关。此外，SHARPIN在控制肺癌细胞转移中起核心作用。机制研究进一步表明，负责催化组蛋白精氨酸甲基化的蛋白精氨酸甲基转移酶5（PRMT5）是SHARPIN的一种新的辅因子。这一发现为进一步研究蛋白质泛素化和组蛋白甲基化之间的相互作用提供了基础。我们进一步发现，SHARPIN-PRMT5对于关键转移相关基因染色质组蛋白的单甲基化至关重要，从而确定了一种调节癌症侵袭的新机制。一种新的混合谱系白血病复合体（ASH2和WDR5）参与组蛋白精氨酸2单甲基化（H3R2me1）和组蛋白赖氨酸4三甲基化（H3K4me3）之间的联系，以激活转移相关基因。这些新发现建立了一种新的表观遗传模式，即SHARPIN-PRMT5通过整合H3R2me1和H3K4me3之间的信号，在协调癌症相关基因的染色质环境中发挥独特作用。
