Carm1

PURPOSE: The purpose of this study was to determine how the intersection of coactivator-associated arginine methyltransferase 1 (CARM1) and biological sex impacts skeletal muscle adaptations to chronic physical activity. METHODS: 12-week-old female (F) and male (M) wild-type (WT) and CARM1 skeletal muscle-specific knockout mice (mKO) were randomly assigned to sedentary (SED) or voluntary wheel running (VWR) experimental groups. For 8 weeks, the animals in the VWR cohort had volitional access to running wheels...

PURPOSE/OBJECTIVE(S): Radiotherapy is commonly applied in multiple cancer types. Besides irradiation induced direct cell death, radiotherapy stimulated significant immune responses for tumor control. Intact and functional cGAS-STING pathway in both tumor cells and host cells is indispensable for efficient irradiation-induced anti-tumor effects. Coactivator-associated arginine methyltransferase 1 (Carm1) is emerging as an attractive therapeutic target and a biomarker for prognosis in various types of cancer...

CARM1 is amplified or overexpressed in many cancer types, and its overexpression correlates with poor prognosis. Potent small-molecule inhibitors for CARM1 have been developed, but the cellular efficacy of the CARM1 inhibitors is limited. We herein report the development of the proteolysis targeting chimera (PROTAC) for CARM1, which contains a CARM1 ligand TP-064, a linker, and a VHL E3 ligase ligand. Compound 3b elicited potent cellular degradation activity (DC50 = 8 nM and D max > 95%) in a few hours. Compound 3b degraded CARM1 in VHL- and proteasome-dependent manner and was highly selective for CARM1 over other protein arginine methyltransferases...

BACKGROUND: The imbalance between osteoblasts and osteoclasts may lead to osteoporosis. Osteoblasts and osteoclasts have different energy requirements, with aerobic glycolysis being the prominent metabolic feature of osteoblasts, while osteoclast differentiation and fusion are driven by oxidative phosphorylation. METHODS: By polymerase chain reaction as well as Western blotting, we assayed coactivator-associated arginine methyltransferase 1 (CARM1) expression in bone tissue, the mouse precranial osteoblast cell line MC3T3-E1 and the mouse monocyte macrophage leukaemia cell line RAW264...

Osteogenic differentiation of mesenchymal cells is controlled by epigenetic enzymes that regulate post-translational modifications of histones. Compared to acetyl or methyltransferases, the physiological functions of protein arginine methyltransferases (PRMTs) in osteoblast differentiation remain minimally understood. Therefore, we surveyed the expression and function of all nine mammalian PRMT members during osteoblast differentiation. RNA-seq gene expression profiling shows that Prmt1, Prmt4/Carm1 and Prmt5 represent the most prominently expressed PRMT subtypes in mouse calvarial bone and MC3T3 osteoblasts as well as human musculoskeletal tissues and mesenchymal stromal cells (MSCs)...

Dysregulation of transcription is a hallmark of cancer, including bladder cancer (BLCA). CRISPR-Cas9 screening using a lentivirus library with single guide RNAs (sgRNAs) targeting human transcription factors and chromatin modifiers is used to reveal genes critical for the proliferation and survival of BLCA cells. As a result, the nuclear transcription factor Y subunit gamma (NFYC)-37, but not NFYC-50, is observed to promote cell proliferation and tumor growth in BLCA. Mechanistically, NFYC-37 interacts with CBP and SREBP2 to activate mevalonate pathway transcription, promoting cholesterol biosynthesis...

Protein arginine methylation is a common post-translational modification involved in the regulation of various cellular functions. Coactivator-associated arginine methyltransferase 1 (CARM1) is a protein arginine methyltransferase that asymmetrically dimethylates histone H3 and non-histone proteins to regulate gene transcription. CARM1 has been found to play important roles in cell differentiation and development, cell cycle progression, autophagy, metabolism, pre-mRNA splicing and transportation, and DNA replication...

CARM1 is an arginine methyltransferase that post-translationally modifies proteins that regulate multiple levels of RNA production and processing. Its substrates include histones, transcription factors, co-regulators of transcription and splicing factors. CARM1 is overexpressed in many different cancer types, and often promotes transcription factor programs that are co-opted as drivers of the transformed cell state, a process known as transcription factor addiction. Targeting these oncogenic transcription factor pathways is difficult but could be addressed by removing the activity of the key coactivators on which they rely...

Prostate cancer (PCa) is a clinically heterogeneous disease with a progressively increasing incidence. Concurrent inhibition of coactivator-associated arginine methyltransferase 1 (CARM1) and histone deacetylase 2 (HDAC2) could potentially be a novel strategy against PCa. Herein, we identified seven compounds simultaneously targeting CARM1 and HDAC2 through structure-based virtual screening. These compounds possessed potent inhibitory activities at the nanomolar level in vitro . Among them, CH-1 was the most active inhibitor which exhibited excellent and balanced inhibitory effects against both CARM1 (IC50 = 3...

Coactivator-associated arginine methyltransferase 1 (CARM1) catalyzes the methylation of arginine residues on target proteins critical for health and disease. The purpose of this study was to characterize the effects of short-term, pharmacological CARM1 inhibition on skeletal muscle size, function, and atrophy. Adult mice (n = 10-11/sex) were treated with either a CARM1 inhibitor (150 mg/kg EZM2302; EZM) or vehicle (Veh) via oral gavage for 11-13 days and muscle mass, function, and exercise capacity were assessed...

BACKGROUND: Multiple myeloma (MM) is a malignant proliferative disease of plasma cells, the incidence of which is increasing every year and remains incurable. The enzyme co-activator-associated arginine methyltransferase 1 (CARM1) is highly expressed in a variety of cancers, such as Hodgkin's lymphoma and acute myeloid leukemia, and CARM1 is closely associated with tumor cell proliferation. However, the role of CARM1 in MM has not been elucidated. METHODS AND RESULTS: In this study, we found that CARM1 is overexpressed in MM and closely associated with poor prognosis in MM...

Bone repair remains a clinical challenge due to low osteogenic capacity. Coactivator associated arginine methyltransferase 1 (CARM1) is a protein arginine methyltransferase that mediates arginine methylation and endochondral ossification. However, the roles of CARM1 in osteoblastic differentiation and bone remodeling have not been explored. In our study, heterozygous CARM1-knockout (KO) mice were generated using the CRISPR-Cas9 system and a model of femoral defect was created. At day 7 postsurgery, CARM1-KO mice exhibited obvious bone loss compared with wild type (WT) mice, as evidenced by reduced bone mineral density (BMD), bone volume/total volume (BV/TV), trabecular thickness (Tb...

1,25-Dihydroxyvitamin D3 (1,25(OH)2 D3 ), the hormonally active form of vitamin D, activates the nuclear vitamin D receptor (VDR) to mediate the transcription of target genes involved in calcium homeostasis as well as in non-classical 1,25(OH)2 D3 actions. In this study, CARM1, an arginine methyltransferase, was found to mediate coactivator synergy in the presence of GRIP1 (a primary coactivator) and to cooperate with G9a, a lysine methyltransferase, in 1,25(OH)2 D3 induced transcription of Cyp24a1 (the gene involved in the metabolic inactivation of 1,25(OH)2 D3 )...

UNLABELLED: The arginine methyltransferase CARM1 exhibits high expression levels in several human cancers, with the trend also observed in ovarian cancer. However, therapeutic approaches targeting tumors that overexpress CARM1 have not been explored. Cancer cells exploit metabolic reprogramming such as fatty acids for their survival. Here we report that CARM1 promotes monounsaturated fatty acid synthesis and fatty acid reprogramming represents a metabolic vulnerability for CARM1-expressing ovarian cancer...

Here, we describe how the speed of C/EBPα-induced B cell to macrophage transdifferentiation (BMT) can be regulated, using both mouse and human models. The identification of a mutant of C/EBPα (C/EBPαR35A ) that greatly accelerates BMT helped to illuminate the mechanism. Thus, incoming C/EBPα binds to PU.1, an obligate partner expressed in B cells, leading to the release of PU.1 from B cell enhancers, chromatin closing and silencing of the B cell program. Released PU.1 redistributes to macrophage enhancers newly occupied by C/EBPα, causing chromatin opening and activation of macrophage genes...

BACKGROUND: Although CircHULC was overexpressed in several cancers, the role of CircHULC in malignancies has yet to be elucidated. METHODS: Gene infection, tumorigenesis test in vitro and in vivo and the signaling pathway analysis were performed. RESULTS: our results indicate that CircHULC promotes growth of human liver cancer stem cells and the malignant differentiation of hepatocyte-like cells. Mechanistically, CircHULC enhances the methylation modification of PKM2 via CARM1 and the deacetylase Sirt1...

BACKGROUND: Necroptosis and pyroptosis, two types of proinflammatory programmed cell death, were recently found to play important roles in spinal cord injury (SCI). Moreover, cyclic helix B peptide (CHBP) was designed to maintain erythropoietin (EPO) activity and protect tissue against the adverse effects of EPO. However, the protective mechanism of CHBP following SCI is still unknown. This research explored the necroptosis- and pyroptosis-related mechanism underlying the neuroprotective effect of CHBP after SCI...

Coactivator-associated arginine methyltransferase 1 (CARM1), a type I protein arginine methyltransferase (PRMT), has been widely reported to catalyze arginine methylation of histone and non-histone substrates, which is closely associated with the occurrence and progression of cancer. Recently, accumulating studies have demonstrated the oncogenic role of CARM1 in many types of human cancers. More importantly, CARM1 has been emerging as an attractive therapeutic target for discovery of new candidate anti-tumor drugs...

Intrauterine smoke (IUS) exposure during early childhood has been associated with a number of negative health consequences, including reduced lung function and asthma susceptibility. The biological mechanisms underlying these associations have not been established. MicroRNAs regulate the expression of numerous genes involved in lung development. Thus, investigation of the impact of IUS on miRNA expression during human lung development may elucidate the impact of IUS on post-natal respiratory outcomes. We sought to investigate the effect of IUS exposure on miRNA expression during early lung development...

BACKGROUND: Neuroinflammation and oxidative stress are important pathological mechanisms underlying cerebral ischemic stroke. Increasing evidence suggests that regulation autophagy in ischemic stroke may improve neurological functions. In this study, we aimed to explore whether exercise pretreatment attenuates neuroinflammation and oxidative stress in ischemic stroke by improving autophagic flux. METHODS: 2,3,5-Triphenyltetrazolium chloride staining was used to determine the infarction volume, and modified Neurological Severity Scores and rotarod test were used to evaluate neurological functions after ischemic stroke...