The emerging role of CARM1 in cancer

Abstract

Coactivator-associated arginine methyltransferase 1 (CARM1), pivotal for catalyzing arginine methylation of histone and non-histone proteins, plays a crucial role in developing various cancers. CARM1 was initially recognized as a transcriptional coregulator by orchestrating chromatin remodeling, transcription regulation, mRNA splicing and stability. This diverse functionality contributes to the recruitment of transcription factors that foster malignancies. Going beyond its established involvement in transcriptional control, CARM1-mediated methylation influences a spectrum of biological processes, including the cell cycle, metabolism, autophagy, redox homeostasis, and inflammation. By manipulating these physiological functions, CARM1 becomes essential in critical processes such as tumorigenesis, metastasis, and therapeutic resistance. Consequently, it emerges as a viable target for therapeutic intervention and a possible biomarker for medication response in specific cancer types. This review provides a comprehensive exploration of the various physiological functions of CARM1 in the context of cancer. Furthermore, we discuss potential CARM1-targeting pharmaceutical interventions for cancer therapy.

Keywords: Arginine methylation; Biomarker; CARM1; Therapeutic target; Tumorigenesis.

Fig. 1

The mammalian PRMTs and related metabolic processes. (a) The universal methyl donor S-adenosyl-methionine (SAM) is enzymatically synthesized from methionine through the catalytic action of methionine adenosyltransferase 2A (MAT2A). SAM is consumed by PRMTs, a subclass of methyltransferases (MTs), to effectuate the methylation of arginine, thereby producing S-adenosyl-homocysteine (SAH). SAH, in turn, undergoes recycling back into methionine by methionine synthase (MS) or used in the transsulfuration pathway for glutathione production. (b) PRMTs exhibit the remarkable capacity to catalyze various methylation reactions on arginine, encompassing monomethylation (MMA), asymmetric dimethylation (ADMA), and symmetric dimethylation (SDMA), all facilitated by SAM as methyl donor. Type I PRMTs, namely PRMT1-4, PRMT6, and PRMT8, predominantly catalyze MMA and ADMA. On the other hand, type II enzymes, PRMT5 and PRMT9, are responsible for catalyzing both MMA and SDMA. Type III, such as PRMT7, specifically mediates the MMA. (c) Eleven distinct PRMTs have been identified, each featuring a typical SAM-dependent MTase catalytic core domain and diverse N-terminal non-catalytic domains. Abbreviations: ADMA, asymmetric dimethylation (ADMA); GSH, reduced glutathione; MAT2A, methionine adenosyltransferase 2A; MMA, monomethylation; MTAP, methylthioadenosine phosphorylase; MTR, methylthioribose; MTs, Methyltransferases, SAH, S-adenosyl-homocysteine (SAH); SAM, S-adenosyl-methionine; SDMA, symmetric demethylation; THF, tetra-hydrofolate

Fig. 2

The overview of CARM1-mediated methylation in oncogenic processes. CARM1 is a sensor for oncogenic signals, nutrients, and oxidative stress, which control tumorigenesis, resistance and metastasis. The overexpressed or overactivated CARM1 catalyzes the methylation of target proteins, which implicates in various pathways, including transcriptional activation, RNA processing, metabolism, redox homeostasis, autophagy and inflammation

Fig. 3

Regulating the activity and function of CARM1 by post-translational modifications. (a) The full-length CARM1 with 608 amino acids has been schematically divided into three domains essential for its function: including the N-terminal domain of CARM1 contains a pleckstrin homology (PH)-like domain with the arginine methyltransferase activity, the C-terminal domain of CARM1 (residues 479–608 in mCARM1) contains multiple motifs involved in protein-protein interactions, and the flexible linker region that contains a catalytic core domain (residues 149–469). Multiple post-translational modifications, like phosphorylation, ubiquitination, methylation, and O-GlcNAcylation, of CARM1 can alter its activity and function in response to various physiological and environmental stimuli. (b) CARM1 has several alternatively spliced isoforms, including the full-length isoform (V1/FL) with 608 aa, V2 isoform with 651 aa, V3 isoform with 573 aa and V4/ΔE15 isoform with 585 aa, respectively. ESRP1 regulates the alternative splicing of CARM1, resulting in reduced CARM1 and increased CARM1ΔE15. The CARM1 protein can be imported by Nup54 into nuclear, where it serves as the transcriptional activator. (c) CARM1 serves as an arginine methyltransferase enzyme writer that adds mono- and asymmetric dimethylation to the arginyl residues in target proteins using SAM as the methyl donor. Demethylases can reversibly demethylate this modification, termed the ‘erasers’. Methylarginines, which regulate the pleiotropic biological functions, are further recognized by ‘readers.’ Abbreviations: ADMA, asymmetric dimethylation; DA, dimerization arm; ESRP1, Epithelial Splicing Regulatory Protein 1; JMJDs, Jumonji C domain-containing proteins; NLS, nuclear localization sequence; Nup54, nucleoporin 54; OGT, O-linked N-acetylglucosamine transferase; PH, pleckstrin homology; TAD, transcriptional activation domain

Fig. 4

CARM1 controls the transcriptional activation in cancer. CARM1-mediated methylation works together with histone acetylation or citrullination to promote transcriptional activation by remodeling chromatin and releasing core repressors from chromatin (a, b). Preacetylation of histone H3 by p300 stimulates methylation of H3R17 by CARM1 (c), whereas citrullination of H3R17 by PADI4 blocks this process (d), creating active open chromatin for transcription. CARM1-mediated histone methylation serves as a platform for recruitment of transcriptional complexes, like p160 (e, h, i), NUMAC (f), BAP1 (g), AETFC (j). In addition, CARM1 modifies key regulatory factors in the transcription complex through methylation, promoting the recruitment of the transcriptional coactivator to enhancers. By promoting gene transcription, CARM1 has been implicated in the pathogenesis and poor prognostic outcomes of several cancers, such as breast cancer (e, f, g), gastric cancer (h), DLBCL (i, j), SCLC (k). CARM1 can also regulate gene transcription in response to extracellular IFN-γ signals (l). Abbreviations: ASXL2, ASXL Transcriptional Regulator 2; BRG1, brahma-regulated gene 1; CBP, CREB-binding protein; E2F1, E2F Transcription Factor 1; ERα, estrogen receptor alpha; ERE, estrogen response element; LYL1, the Lymphoblastic leukemia 1; NFIB, nuclear factor I B; MLL3, mixed-lineage leukemia 3; PADI4, peptidylarginine deiminase IV; SRC-3, steroid receptor coactivator-3; TAL1, T cell acute lymphocytic leukemia 1; TRIM29, tripartite motif containing 29

Fig. 5

CARM1 controls autophagy, metabolism and redox homeostasis in tumors. In normal condition, the nuclear CARM1 was degraded by the UPS. During prolonged nutrient starvation, activated AMPK phosphorylates FOXO3, leading to the transcriptional repression of SKP2 and reduced degradation of CARM1. Elevated CARM1 increases H3R17me2, thereby activating the TFEB or TRE3-mediated autophagy and lysosomal gene transcription, which are crucial for developing resistance to chemotherapy. The methylation of Nrf2 by CARM1 limits its nuclear translocation and, subsequently, the transcription of GPX4, accelerating oxidative damage. CARM1 coordinates the transcriptional reprogramming of metabolic pathways, such as altering the expression AMPK and PGAM2 in glycolysis, as well as ACC1, SCD1 and FASN in de novo lipogenesis. CARM1 exhibits regulatory roles across various metabolic pathways, encompassing glutamine metabolism, glycolysis, OXPHOS, the pentose phosphate pathway, and lipid metabolism. The CARM1-dependent methylation of PKM2 reduces InsP3R expression, shifting metabolism from OXPHOS to aerobic glycolysis. In liver cancer cells, AMPK-dependent upregulation of CARM1 during glucose starvation inhibits glycolysis through GAPDH methylation. Methylation of MDH1 by CARM1 inhibits its activity, suppressing glutamine metabolism under normal conditions. Conversely, ROS-induced inhibition of CARM1 activates glutamine metabolism under stress conditions in PDAC. Additionally, CARM1 regulates the cellular redox homeostasis. CARM1-mediated metabolism also adapts tumor cells to variable oxidative stress conditions. Notably, the RPIA and MDH1 are methylated by CARM1, altering the production of NADPH and the cellular redox source. Abbreviations: UPS, ubiquitin-proteasome system; ACC1, acetyl coenzyme A carboxylase 1; CUL1, Cullin-1; FASN, fatty acid synthase; FOXO, Forkhead box-containing protein; GAPDH, Glyceraldehyde 3-phosphate dehydrogenase; InsP3Rs, inositol-1,4,5-trisphosphate receptors; MDH1, malate dehydrogenase 1; OXPHOS, oxidative phosphorylation; PGAM2, Phosphoglycerate mutase 2; PKM2, pyruvate kinase M2; ROS, reactive oxygen species; RPIA, Ribose 5-Phosphate Isomerase; SCD1, stearoyl-CoA desaturase 1; Skp2, S-phase kinase-associated protein 2; TFE3, Transcription factor E3; TFEB, Transcription factor EB