PRMT6 serves an oncogenic role in lung adenocarcinoma via regulating p18

Abstract

lung adenocarcinoma (luad), a major subtype of lung cancer, is the leading cause of cancer-related mortality worldwide. Previous studies have determined the role of the protein arginine methyltransferases (PrMTs) in the physiology and pathology of luad. However, to the best of our knowledge, no empirical studies have been performed determining the association between protein arginine methyltransferase 6 (PrMT6) and luad. The present study aimed to determine the expression levels of PrMT6 in luad and its association with the clinicopathological characteristics. The effect of PrMT6 knockdown on cell growth was analyzed and chromatin immunoprecipitation (chiP) assay was used to investigate the regulatory mechanisms of PrMT6 on downstream gene expression. in addition, a xenograft model was used to determine whether the PrMT6-regulated expression levels of p18 in vitro could be validated in vivo. PrMT6 overexpression in luad is associated with high clinical stage, lymph node metastasis and poor clinical outcomes. Furthermore, the silencing of PRMT6 significantly reduced the enrichment of Histone H3 asymmetric demethylation at arginine 2 in the promoter region of the p18 gene, thereby activating the expression of the gene. This, in turn, induced G1/S phase cell cycle arrest, resulting in the inhibition of cell proliferation. The xenograft model also suggested that PrMT6 suppressed luad development by activating p18 expression in vivo. In conclusion, the findings of the present study suggested that PrMT6 may serve as an oncogene in the progression of luad through epigenetically suppressing p18 expression. Thus, PrMT6 may represent a novel potential therapeutic target for luad.

miR-1307 promotes hepatocarcinogenesis by CALR-OSTC-endoplasmic reticulum protein folding pathway

“…The deletion of RB gene and the deletion of expression of pRB are often observed in cancer such as esophageal squamous cell carcinoma ( Wang et al., 2012 ). P18 has the function of tumor suppressor and also shows the inhibitory activity of PD-1/PD-L1 ( Tang et al., 2020 ). PCNA has been reported to be highly expressed in many cancers, such as non-small-cell lung cancer, breast cancer, etc.…”

Protein arginine methyltransferases: promising targets for cancer therapy

“…PRMT6 regulates the cell cycle via epigenetic repression of cell cycle-related regulators, such as p21 WAF1 , p27 KIP1 , and p18 40 – 42 . The H3R2me2a modification mediated by PRMT6 transcriptionally turns off these genes and, in turn, induces abnormal bypass of the cell cycle.…”

Structure, Activity and Function of the Protein Arginine Methyltransferase 6

“…PRMT6 interacts with interleukin enhancer binding protein 2 (ILF2) and activates the tumor associated macrophages [ 175 ]. PRMT6 levels are higher in the lung tissues of the patients with lung adenocarcinoma, which is associated with poor clinical outcomes [ 176 ]. Increased levels of PRMT6 reduces the expression of the cell cycle regulator p18 by increasing the amount of H3R2me2a and reducing the levels of H3K4me3 modifications.…”

“…Increased levels of PRMT6 reduces the expression of the cell cycle regulator p18 by increasing the amount of H3R2me2a and reducing the levels of H3K4me3 modifications. Depletion of PRMT6 activates the expression of p18 and inhibits the proliferation of lung adenocarcinoma cells [ 176 ].…”

“…Not surprisingly, downregulation of PRMT6 across these cancer types leads to a reduction in cell proliferation and invasiveness through different mechanisms ( Figure 4 ). Depletion or knock-out of PRMT6 reduced (i) the cell proliferation and clonogenic capacity of the breast cancer cells [ 169 ], (ii) the cell migration and invasiveness of prostate cancer cells [ 172 ], (iii) endometrial cancer cell proliferation and migration [ 173 ], (iv) proliferation of lung adenocarcinoma cells [ 176 ] and (v) tumorigenic properties of gastric cancer cells [ 180 ]. It was reported that the inhibition of PRMT6 activity by the PRMT6 specific inhibitor EPZ020411 reduces the tumorigenicity of glioblastoma and improves its response to radiotherapy [ 23 ].…”