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.
Highlights
Lung cancer is one of the leading lethal cancers worldwide
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
Elevated SHARPIN expression was found in both human lung adenocarcinoma and squamous cell carcinoma compared with that in normal lung samples (Figure 1A). This exciting observation was supported by results showing that SHARPIN RNA and protein expression is increased in several common lung cancer cell lines compared with those in normal lung cells (Figure 1B)
Summary
Lung cancer is one of the leading lethal cancers worldwide. The underlying mechanisms of this deadly cancer remain largely unknown [1, 2]. Better elucidation of the pathologic mechanisms involved in lung cancer metastasis will enable the development of better treatment options for patients. SHARPIN (Shank-associated RH domain interacting protein) is the main component of the linear ubiquitin chain activation complex (LUBAC), which gives rise to linear-type ubiquitin chains via linkages between methionine 1 and glycine 76 in proteins [3, 4]. LUBAC has been found to add a linear polyubiquitin chain to IkB kinase (IKK) complex to activate nuclear factor-κB (NFκB) signaling. Linear ubiquitination is involved in the regulation of inflammation and immune signaling [5]
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