Abstract
BackgroundProtein arginine methyltransferase 5 (PRMT5), a type II PRMT, is highly expressed in some tumors, but its role in hepatocellular carcinoma (HCC) is still unknown.MethodsPRMT5 level in HCC specimens was determined by immunohistochemical staining and the association with clinicopathologic features was evaluated. PRMT5 was inhibited by AMI-1 (a small molecule inhibitor of PRMTs) or small interference RNA (siRNA). The proliferation of HCC cells was tested by Cell Counting Kit-8, cell migration was evaluated by Transwell assay and cell cycle and apoptosis were analyzed by flow cytometry. The effect of AMI-1 on HCC in vivo was examined by mouse xenograft model.ResultsPRMT5 expression was markedly upregulated in HCC tissues, and correlated inversely with overall patient survival. Knockdown of PRMT5 significantly reduced the proliferation of HCC cells, but did not affect the growth of normal liver cells. Furthermore, β-catenin was identified as a target of PRMT5. Silencing PRMT5 significantly down-regulated the expression of β-catenin and the downstream effector Cyclin D1 in HCC cells. AMI-1 strongly inhibited HCC growth in vivo, increased the ratio of Bax/Bcl-2, and led to apoptosis and loss of migratory activity in several HCC cells. Meanwhile, AMI-1 decreased the expression levels of symmetric dimethylation of H4 (H4R3me2s), a histone mark of PRMT5.ConclusionsPRMT5 plays an important role in HCC. PRMT5 may be a promising target for HCC therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0721-8) contains supplementary material, which is available to authorized users.
Highlights
Protein arginine methyltransferase 5 (PRMT5), a type II PRMT, is highly expressed in some tumors, but its role in hepatocellular carcinoma (HCC) is still unknown
We showed that PRMT5 protein is overexpressed in HCC tumor tissues, and its elevated level is associated with worse prognosis in patients with HCC
We demonstrate that the deletion of PRMT5 significantly down-regulates the expression of β-catenin and its downstream effector Cyclin D1 in HCC cells
Summary
Protein arginine methyltransferase 5 (PRMT5), a type II PRMT, is highly expressed in some tumors, but its role in hepatocellular carcinoma (HCC) is still unknown. Hepatocellular carcinoma (HCC) is the fifth leading cancer and the third most common cause for cancer death worldwide [1,2,3]. The overall survival of patients with HCC is less than 10 %. A majority of patients with HCC present with advanced. Protein arginine methyltransferase 5 (PRMT5), a type II arginine methyltransferase, is localized in both cytoplasm and the nucleus of mammalian cells [7, 8]. PRMT5-driven methylation of arginine residues leads to symmetric dimethylation of histone H3 (H3R8me2s) and H4 (H4R3me2s), which in turn alter chromatin structure to regulate gene expression [9, 10].
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