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CFLAR , also known as c-FLIP , is a critical anti-apoptotic protein that inhibits activation of caspase 8 in mammalian cells. Previous studies have shown that arginine 122 of CFLAR can be mono-methylated. However, the precise role of arginine methyltransferase of CFLAR remains unknown. PRMT5 and PRMT1, which are important members of the PRMT family, catalyze the transfer of methyl groups to the arginine of substrate proteins. PRMT5 can monomethylate or symmetrically dimethylate arginine residues, while PRMT1 can monomethylate or asymmetrically dimethylate arginine residues. Lung cancer cells were cultured following the standard protocol and the cell lysates were prepared to detect the given proteins by Western Blot analysis, and the protein interaction was assayed by co-immunoprecipitation (Co-IP) or GST pull-down assay. CFLAR ubiquitination level was evaluated by proteasomal inhibitor treatment combined with HA-Ub transfection and WB assay. PRMT1 and PRMT5 genes were knocked down by siRNA technique. We show that PRMT5 up-regulated the protein levels of CFLAR by decreasing the ubiquitination and increasing its protein level. Additionally, PRMT1 down-regulated the protein level of CFLAR by increasing the ubiquitination and degradation. The overexpression of PRMT5 can inhibit the interaction between CFLAR and ITCH, which has been identified as an E3 ubiquitin ligase of CFLAR , while overexpressed PRMT1 enhances the interaction between CFLAR and ITCH. Furthermore, we verified that dead mutations of PRMT5 or PRMT1 have the same effects on CFLAR as the wild-type ones have, suggesting it is the physical interaction between CFLAR and PRMT1/5 that regulates CFLAR degradation other than its enzymatic activity. Finally, we showed that PRMT5 and PRMT1 could suppress or facilitate apoptosis induced by doxorubicin or pemetrexed by affecting CFLAR in NSCLC cells. PRMT5 and PRMT1 mediate the distinct effects on CFLAR degradation by regulating the binding of E3 ligase ITCH in NSCLC cells. This study identifies a cell death mechanism that is fine-tuned by PRMT1/5 that modulate CFLAR degradation in human NSCLC cells.

Protein arginine methyltransferase 1 (PRMT1), the predominant type I protein arginine methyltransferase, plays a crucial role in normal biological functions by catalyzing the methylation of arginine side chains, specifically monomethylarginine (MMA) and asymmetric dimethylarginine (ADMA), within proteins. Recent investigations have unveiled an association between dysregulated PRMT1 expression and the initiation and progression of tumors, significantly impacting patient prognosis, attributed to PRMT1’s involvement in regulating various facets of tumor cell biology, including DNA damage repair, transcriptional and translational regulation, as well as signal transduction. In this review, we present an overview of recent advancements in PRMT1 research across different tumor types, with a specific focus on its contributions to tumor cell proliferation, metastasis, invasion, and drug resistance. Additionally, we expound on the dynamic functions of PRMT1 during distinct stages of cancer progression, elucidating its unique regulatory mechanisms within the same signaling pathway and distinguishing between its promotive and inhibitory effects. Importantly, we sought to provide a comprehensive summary and analysis of recent research progress on PRMT1 in tumors, contributing to a deeper understanding of its role in tumorigenesis, development, and potential treatment strategies.

[This corrects the article DOI: 10.3389/fphar.2025.1721188.].

Reactive oxygen species (ROS) are well-known accelerants of aging, but, paradoxically, we show that physiological levels of ROS extend life span in pupae of themoth Helicoverpa armigera, resulting in the dormant state of diapause. This developmental switch appears to operate through a variant of the conventional insulin-signaling pathway, as evidenced by the facts that Akt, p-Akt, and PRMT1 are elevated by ROS, but not insulin, and that high levels of p-Akt fail to phosphorylate FoxO through PRMT1-mediated methylation. These results suggest a distinct signaling pathway culminating in the elevation of FoxO, which in turn promotes the extension of life span characteristic of diapause.

[This corrects the article DOI: 10.3389/fimmu.2023.1239614.].[This corrects the article DOI: 10.3389/fimmu.2023.1239614.].

Background Aberrant changes in epigenetic mechanisms such as histone modifications play an important role in cancer progression. PRMT1 which triggers asymmetric dimethylation of histone H4 on arginine 3 (H4R3me2a) is upregulated in human colorectal cancer (CRC) and is essential for cell proliferation. However, how this dysregulated modification might contribute to malignant transitions of CRC remains poorly understood. Methods In this study, we integrated biochemical assays including protein interaction studies and chromatin immunoprecipitation (ChIP), cellular analysis including cell viability, proliferation, colony formation, and migration assays, clinical sample analysis, microarray experiments, and ChIP-Seq data to investigate the potential genomic recognition pattern of H4R3me2s in CRC cells and its effect on CRC progression. Results We show that PRMT1 and SMARCA4, an ATPase subunit of the SWI/SNF chromatin remodeling complex, act cooperatively to promote colorectal cancer (CRC) progression. We find that SMARCA4 is a novel effector molecule of PRMT1-mediated H4R3me2a. Mechanistically, we show that H4R3me2a directly recruited SMARCA4 to promote the proliferative, colony-formative, and migratory abilities of CRC cells by enhancing EGFR signaling. We found that EGFR and TNS4 were major direct downstream transcriptional targets of PRMT1 and SMARCA4 in colon cells, and acted in a PRMT1 methyltransferase activity-dependent manner to promote CRC cell proliferation. In vivo, knockdown or inhibition of PRMT1 profoundly attenuated the growth of CRC cells in the C57BL/6 J-Apc Min/+ CRC mice model. Importantly, elevated expression of PRMT1 or SMARCA4 in CRC patients were positively correlated with expression of EGFR and TNS4, and CRC patients had shorter overall survival. These findings reveal a critical interplay between epigenetic and transcriptional control during CRC progression, suggesting that SMARCA4 is a novel key epigenetic modulator of CRC. Our findings thus highlight PRMT1/SMARCA4 inhibition as a potential therapeutic intervention strategy for CRC. Conclusion PRMT1-mediated H4R3me2a recruits SMARCA4, which promotes colorectal cancer progression by enhancing EGFR signaling.

PRMT1, the major protein arginine methyltransferase in mammals, catalyzes monomethylation and asymmetric dimethylation of arginine side chains in proteins. Initially described as a regulator of chromatin dynamics through the methylation of histone H4 at arginine 3 (H4R3), numerous non-histone substrates have since been identified. The variety of these substrates underlines the essential role played by PRMT1 in a large number of biological processes such as transcriptional regulation, signal transduction or DNA repair. This review will provide an overview of the structural, biochemical and cellular features of PRMT1. After a description of the genomic organization and protein structure of PRMT1, special consideration was given to the regulation of PRMT1 enzymatic activity. Finally, we discuss the involvement of PRMT1 in embryonic development, DNA damage repair, as well as its participation in the initiation and progression of several types of cancers.

Background/Aims: Cholangiocarcinoma (CCA) is a primary malignant neoplasm with an extremely poor prognosis. While combined chemoradiotherapy has been demonstrated to delay CCA progression to a certain extent, the absence of specific molecular biomarkers or targets significantly hinders the diagnosis and treatment of CCA. Methods: Through cross-analysis of proteomics and ADMA modificationomics, we identified DDX1 overexpressed in CCA with elevated R602-ADMA modifications. HPLC-MS/MS identified PRMT1 as the methyltransferase and USP10 as the deubiquitinating enzyme for DDX1. Immunofluorescence and nuclear-cytoplasmic partitioning experiments confirmed DDX1’s nuclear localization. GO and KEGG analyses clarify the biological functions of DDX1 in response to hypoxia. RNA-seq transcriptomics analyzed key pathways influenced by DDX1. A hydrodynamic in situ CCA mouse model was established to validate the chemopreventive effects of the PRMT1-specific inhibitor GSK715 on CCA development. Results: DDX1 promotes CCA progression both in vivo and in vitro and can be inhibited by GSK715. Mechanistically, PRMT1 mediates ADMA modification at position R602 of DDX1. This modification promotes DDX1 nuclear localization by recruiting USP10 to deubiquitinate DDX1, while simultaneously inhibiting PRMT1 degradation. DDX1 promotes the transcription of PRMT1 and USP10 by binding to the mRNA 3’UTR region, establishing a positive feedback regulatory pathway. This mechanism promotes the occurrence and development of CCA and can serve as a target for the inhibitor GSK715 to suppress CCA progression. Conclusions: Our study identified DDX1-R602-ADMA modification as a novel ADMA modification in CCA. It further confirmed its pivotal role in CCA progression. Targeting the USP10-PRMT1-DDX1 axis may represent a significant therapeutic approach for CCA. (Clin Mol Hepatol 2026;32:843-865)

This study aims to investigate the mechanism of action of arsenic-based agents against hepatocellular carcinoma (HCC) and to identify effective drug targets for HCC treatment. Huh7 and HepG2 cells treated with NaAsO2 were assessed for cell viability, pyroptosis, migration, and invasion after undergoing lentiviral transfection. An orthotopic liver tumor model was established and divided into a model group and a treatment group. Proteins associated with QRICH1, PRMT1, cGAS-STING, and the classical pyroptosis pathway were quantified using Western blotting. The intracellular expression and localization of PRMT1 and NLRP3 in HCC were analyzed through cellular immunofluorescence. Co-immunoprecipitation (Co-IP) was performed to examine the protein interactions between PRMT1 and cGAS, as well as between STING and NLRP3. Chromatin immunoprecipitation (ChIP) was used to confirm QRICH1 enrichment in the PRMT1 promoter region. NaAsO2 treatment significantly inhibited the proliferation of Huh7 and HepG2 cells and effectively blocked their migration and invasion capabilities, while promoting cellular pyroptosis. Quantitative polymerase chain reaction(QRCR) and ChIP assays confirmed that NaAsO2 regulates PRMT1 expression by down-regulate QRICH1 binding in the PRMT1 promoter region. Additionally, NaAsO2 decreased the expression of the QRICH1-PRMT1 complex and upregulated the cGAS-STING signaling pathway, activating the downstream NLRP3-dependent classical pyroptosis pathway. Overexpression of QRICH1 reversed these effects. NaAsO2 inhibits the expression of the QRICH1-PRMT1 axis, activates cGAS-STING signaling pathway transduction, and induces pyroptosis in HCC cells, thereby increasing the infiltration of immune cells in liver cancer tissues.

The microbiota and bacterial metabolites in the colon are regarded as alternative targets for colon cancer prevention and therapy. Among these metabolites, short-chain fatty acids (SCFAs) exhibit anticancer effects and suppress inflammation in the colon. However, the molecular mechanisms and target development of SCFAs require additional study. In the present study, using RNA-seq results from colon cancer samples derived from the Cancer Genome Atlas (TCGA) portal, overexpressed epigenetic modifiers were identified and RT-PCR and qRT-PCR analysis was performed to select target genes that responded to treatment with propionate in HCT116 cells. Downregulation of protein arginine methyltransferase 1 (PRMT1), a histone arginine methyltransferase, was observed after sodium propionate (SP) treatment. Moreover, phospho-array analysis demonstrated that the mTOR pathway was involved in propionate and siPRMT1 treatment, and regulation of this pathway was associated with apoptosis in HCT116 cells. The present study, to the best of our knowledge, was the first to demonstrate that PRMT1 levels were reduced by propionate treatment in HCT116 cells and that downregulation of PRMT1 induced cell apoptosis. Thus, this novel mechanism of sodium propionate treatment for colon cancer therapy may indicate more effective approaches, such as dietary therapy, for CRC patients.