Oncotarget

Research Papers:

A novel SHARPIN-PRMT5-H3R2me1 axis is essential for lung cancer cell invasion

Tingxiong Fu, Xiuwei Lv, Qingzhi Kong and Changjing Yuan _

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Oncotarget. 2017; 8:54809-54820. https://doi.org/10.18632/oncotarget.18957

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Abstract

Tingxiong Fu1,*, Xiuwei Lv2,*, Qingzhi Kong3 and Changjing Yuan2

1Department of Pharmacy, The Central Hospital of Wuhan, Tongji Medical School, Huazhong University of Science and Technology, Wuhan, Hubei, China

2Department 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

3The Central Hospital of Wuhan, Tongji Medical School, Huazhong University of Science and Technology, Wuhan, Hubei, China

*These authors contributed equally to this work

Correspondence to:

Changjing Yuan, email: [email protected]

Keywords: SHARPIN, PRMT5, cancer invasion, histone modification, gene expression

Received: May 16, 2017     Accepted: June 16, 2017     Published: July 04, 2017

ABSTRACT

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.


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