Protein arginine methyltransferases: promising targets for cancer therapy

Abstract

Protein methylation, a post-translational modification (PTM), is observed in a wide variety of cell types from prokaryotes to eukaryotes. With recent and rapid advancements in epigenetic research, the importance of protein methylation has been highlighted. The methylation of histone proteins that contributes to the epigenetic histone code is not only dynamic but is also finely controlled by histone methyltransferases and demethylases, which are essential for the transcriptional regulation of genes. In addition, many nonhistone proteins are methylated, and these modifications govern a variety of cellular functions, including RNA processing, translation, signal transduction, DNA damage response, and the cell cycle. Recently, the importance of protein arginine methylation, especially in cell cycle regulation and DNA repair processes, has been noted. Since the dysregulation of protein arginine methylation is closely associated with cancer development, protein arginine methyltransferases (PRMTs) have garnered significant interest as novel targets for anticancer drug development. Indeed, several PRMT inhibitors are in phase 1/2 clinical trials. In this review, we discuss the biological functions of PRMTs in cancer and the current development status of PRMT inhibitors in cancer therapy.

PRMT4 promotes hepatocellular carcinoma progression by activating AKT/mTOR signaling and indicates poor prognosis

“…This posttranslational modification is mainly catalyzed by the protein arginine methyltransferase (PRMT) family. PRMTs, composed of nine members, can be divided into three types (I, II and III) based on their catalytic activity: type I PRMTs (PRMT1, 2, 3, 4, 6, and 8) are responsible for asymmetric dimethylarginine (ADMA) and monomethylarginine (MMA), type II PRMTs (PRMT5 and 9) generate symmetric dimethylarginine (SDMA) and MMA, and type III PRMT (PRMT 7) catalyze the formation of MMA 6 , 7 . Since the dysregulation of protein arginine methylation is closely related to the development of cancer, PRMTs, as novel anticancer drug development targets, have attracted increasing attention 6 , 8 , 9 .…”

Combining Human Genetics of Multiple Sclerosis with Oxidative Stress Phenotype for Drug Repositioning

“…The drug mechanism responsible for CARM1 inhibition has not yet been defined, and there is the possibility that it acts indirectly via the inhibition of HSP90, which was identified as a CARM1 interactor (EP 3 208 615 B1). In addition, we also indicated highly selective inhibitors of CARM1, recently developed and tested in experimental models [62][63][64]. PEITC is an organosulfur bioactive compound, known as an MAPK1 activator, that is currently in trial for lung cancer and leukemia treatment (NCT00691132 and NCT00968461).…”

Naturally occurring cancer-associated mutations disrupt oligomerization and activity of protein arginine methyltransferase 1 (PRMT1)

“…The reactions catalyzed by PRMT1 are crucial for maintaining cellular health, and dysregulated PRMT1 contributes to the pathology of several cancers ( 14 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ). In this study we identified three mechanistically relevant dimer arm mutations by screening mutations that occur in human cancers.…”

“…This enzyme targets numerous proteins involved in epigenetic and transcriptional regulation such as histone H4 ( 17 , 18 ), the estrogen receptor ( 19 , 20 ), and the progesterone receptor ( 21 ). Upregulation of PRMT1 is observed in many cancer types and often correlates with cancer grade and poor patient prognosis ( 14 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ), and there are a growing number of studies suggesting that PRMT1 is an important regulator in many pathways that are dysregulated in cancers ( 14 , 26 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ). While it is clear that PRMT overexpression is deleterious in many diseases, it is also clear that maintaining some level of arginine methylation is critical for cellular and organismal health.…”