Protein arginine N-methyltransferase 6 (PRMT6) (PRMT6)

Protein arginine N-methyltransferase 6 (PRMT6) is a type I PRMT enzyme that primarily localizes to the nucleus and catalyzes the asymmetric dimethylation of arginine residues on histone and non-histone substrates [1, 2]. Its primary epigenetic role involves the methylation of histone H3 at arginine 2 (H3R2me2a), a modification that typically functions as a transcriptional repressor by antagonizing the activation-associated H3K4me3 mark [2, 8]. PRMT6 is involved in a variety of critical cellular processes, including the regulation of the cell cycle, DNA repair through the methylation of DNA polymerase beta, and the modulation of viral transactivation, such as the methylation of the HIV-1 Tat protein [1, 9]. In many human malignancies, including lung, bladder, and prostate cancers, PRMT6 is overexpressed and acts as an oncogene by promoting cell proliferation and inhibiting senescence through the repression of tumor suppressors like p21 and p27 [1, 13]. Due to its significant role in tumor progression and drug resistance, PRMT6 has become an attractive therapeutic target in oncology [1, 5]. Several small-molecule inhibitors, including selective allosteric and covalent modulators like SGC6870 and MS117, have been developed to explore the therapeutic potential of PRMT6 inhibition [10, 11, 14]. However, the context-specific nature of PRMT6, which can act as a tumor suppressor in certain cancers like melanoma, presents a challenge for broad clinical application [2, 16].

Other names

HRMT1L6Heterogeneous nuclear ribonucleoprotein methyltransferase-like protein 6Histone-arginine N-methyltransferase PRMT6FLJ10559HMT1 HnRNP Methyltransferase-Like 6

PRMT6 inhibitors act by binding to the catalytic site or an allosteric pocket of the enzyme, thereby preventing the transfer of a methyl group from S-adenosyl-L-methionine (SAM) to arginine residues on substrate proteins [1, 12]. This inhibition leads to a reduction in asymmetric dimethylation (ADMA) levels, particularly H3R2me2a, which can restore the expression of silenced tumor suppressor genes and disrupt oncogenic signaling pathways [2, 13].