Protein Arginine Methylation: An Emerging Modification in Cancer Immunity and Immunotherapy

Abstract

In recent years, protein arginine methyltransferases (PRMTs) have emerged as new members of a gene expression regulator family in eukaryotes, and are associated with cancer pathogenesis and progression. Cancer immunotherapy has significantly improved cancer treatment in terms of overall survival and quality of life. Protein arginine methylation is an epigenetic modification function not only in transcription, RNA processing, and signal transduction cascades, but also in many cancer-immunity cycle processes. Arginine methylation is involved in the activation of anti-cancer immunity and the regulation of immunotherapy efficacy. In this review, we summarize the most up-to-date information on regulatory molecular mechanisms and different underlying arginine methylation signaling pathways in innate and adaptive immune responses during cancer. We also outline the potential of PRMT-inhibitors as effective combinatorial treatments with immunotherapy.

Classification molecular subtypes of hepatocellular carcinoma based on PRMT-related genes

“…Despite great advances for immunotherapy in cancers, the majority of patients relapse or fail to response to immunotherapy due to insufficient immune response against tumors or suppressive tumor microenvironment (TME) (Falcomatà et al, 2023). PRMTs have been elucidated as key factor in tumor immunosurveillance of TME (Dai et al, 2022;Fedoriw et al, 2022). Here, the molecular tool constructed in our study had excellent predictive ability in immunotherapy efficacy and drug sensitivity of HCC.…”

“…Protein arginine methylation, catalyzed by protein arginine methyltransferases (PRMTs), is emerging as a critical posttranslational modification (PTM) in various cell biological processes, such as epigenetic regulation, DNA damage response and immune surveillance (Jarrold and Davies, 2019;Dai et al, 2022). Generally, PRMT family enzymes serve as "writers" of PTM, are classified into three types according to the specificity of product: type I PRMTs (PRMT1, PRMT2, PRMT3, PRMT4, PRMT6, and PRMT8) mainly generate asymmetric arginine demethylation (aDMA); type II PRMTs including PRMT5 and PRMT9 that catalyze the formation of symmetric arginine dimethylation (sDMA).…”

“…Generally, PRMT family enzymes serve as "writers" of PTM, are classified into three types according to the specificity of product: type I PRMTs (PRMT1, PRMT2, PRMT3, PRMT4, PRMT6, and PRMT8) mainly generate asymmetric arginine demethylation (aDMA); type II PRMTs including PRMT5 and PRMT9 that catalyze the formation of symmetric arginine dimethylation (sDMA). PRMT7, identified as type III PRMTs, catalyzes MMA only (Al-Hamashi et al, 2020;Wang et al, 2021;Dai et al, 2022). Recently, aberrant methylation of arginine residues has been implicated in several malignancies and the ectopic expression of PRMTs has been demonstrated in multiple types of tumors including HCC (Elakoum et al, 2014;Hernandez et al, 2017;Zhong et al, 2018;Song et al, 2020;Lei et al, 2022).…”

Protein posttranslational modifications in health and diseases: Functions, regulatory mechanisms, and therapeutic implications

“…Aberrant methylation is closely associated with the occurrence and development of cancer. 734 Compared with normal tissues, PRMT1, PRMT4, and PRMT6 showed higher expression in lung cancer tissues. 777 , 778 Similarly, PRMT1, PRMT2, PRMT3, PRMT4, and PRMT7 are highly expressed in breast cancer tissues.…”

“… 733 Some immunomodulatory proteins, such as Vav1 and NIP45, can also be modified by arginine methylation. 734 In addition, KMT1C, KMT1D, and KMT1E in the KMT1 family; KMT2F in the KMT2 family; KMT3B, KMT3C, and KMT3E in the KMT3 family; KMT5A in the KMT5 family; and KMT7 have also been reported to catalyze nonhistone lysine methylation. 735 , 736 , 737 , 738 For example, KMT3C/SMYD2 methylates Rb at Lys860.…”