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Chronic varicella zoster virus (VZV) infection induced neuroinflammatory condition is the critical pathology of post-herpetic neuralgia (PHN). The immune escape mechanism of VZV remains elusive. As to mice have no VZV infection receptor, herpes simplex virus type 1 (HSV-1) infection is a well established PHN mice model. Transcriptional expression analysis identified that the protein arginine methyltransferases 6 (Prmt6) was upregulated upon HSV-1 infection, which was further confirmed by immunofluorescence staining in spinal dorsal horn. Prmt6 deficiency decreased HSV-1-induced neuroinflammation and PHN by enhancing antiviral innate immunity and decreasing HSV-1 load in vivo and in vitro. Overexpression of Prmt6 in microglia dampened antiviral innate immunity and increased HSV-1 load. Mechanistically, Prmt6 methylated and inactivated STING, resulting in reduced phosphorylation of TANK binding kinase-1 (TBK1) and interferon regulatory factor 3 (IRF3), diminished production of type I interferon (IFN-I) and antiviral innate immunity. Furthermore, intrathecal or intraperitoneal administration of the Prmt6 inhibitor EPZ020411 decreased HSV-1-induced neuroinflammation and PHN by enhancing antiviral innate immunity and decreasing HSV-1 load. Our findings revealed that HSV-1 escapes antiviral innate immunity and results in PHN by upregulating Prmt6 expression and inhibiting the cGAS-STING pathway, providing novel insights and a potential therapeutic target for PHN. [ABSTRACT FROM AUTHOR]

Background: Protein arginine methyltransferase 6 (PRMT6) plays a crucial role in various pathophysiological processes and diseases. Glioblastoma (GBM; WHO Grade 4 glioma) is the most common and lethal primary brain tumor in adults, with a prognosis that is extremely poor, despite being less common than other systemic malignancies. Our current research finds PRMT6 upregulated in GBM, enhancing tumor malignancy. Yet, the specifics of PRMT6's regulatory processes and potential molecular mechanisms in GBM remain largely unexplored. Methods: PRMT6's expression and prognostic significance in GBM were assessed using glioma public databases, immunohistochemistry (IHC), and immunoblotting. Scratch and Transwell assays examined GBM cell migration and invasion. Immunoblotting evaluated the expression of epithelial-mesenchymal transition (EMT) and Wnt-β-catenin pathway-related proteins. Dual-luciferase reporter assays and ChIP-qPCR assessed the regulatory relationship between PRMT6 and YTHDF2. An in situ tumor model in nude mice evaluated in vivo conditions. Results: Bioinformatics analysis indicates high expression of PRMT6 and YTHDF2 in GBM, correlating with poor prognosis. Functional experiments show PRMT6 and YTHDF2 promote GBM migration, invasion, and EMT. Mechanistic experiments reveal PRMT6 and CDK9 co-regulate YTHDF2 expression. YTHDF2 binds and promotes the degradation of negative regulators APC and GSK3β mRNA of the Wnt-β-catenin pathway, activating it and consequently enhancing GBM malignancy. Conclusions: Our results demonstrate the PRMT6-YTHDF2-Wnt-β-Catenin axis promotes GBM migration, invasion, and EMT in vitro and in vivo, potentially serving as a therapeutic target for GBM. [ABSTRACT FROM AUTHOR]

AMP-activated protein kinase (AMPK) is a heterotrimeric serine/threonine kinase comprising α, β, and γ subunits. AMPK is involved in intracellular energy metabolism and functions as a switch that turns various biological pathways in eukaryotes on and off. Several post-translational modifications regulating AMPK function have been demonstrated, including phosphorylation, acetylation, and ubiquitination; however, arginine methylation has not been reported in AMPKα1. We investigated whether arginine methylation occurs in AMPKα1. Screening experiments revealed arginine methylation of AMPKα1 mediated by protein arginine methyltransferase 6 (PRMT6). In vitro methylation and co-immunoprecipitation assays indicated that PRMT6 can directly interact with and methylate AMPKα1 without involvement of other intracellular components. In vitro methylation assays with truncated and point mutants of AMPKα1 revealed that Arg403 is the residue methylated by PRMT6. Immunocytochemical studies showed that the number of AMPKα1 puncta was enhanced in saponin-permeabilized cells when AMPKα1 was co-expressed with PRMT6, suggesting that PRMT6-mediated methylation of AMPKα1 at Arg403 alters the physiological characteristics of AMPKα1 and may lead to liquid-liquid phase separation. [Display omitted] • Protein arginine methyltransferase 6 (PRMT6) directly methylates AMPKα1. • Arginine 403 of AMPKα1 is the residue methylated by PRMT6. • This event may contribute to the formation of the phase-separated puncta. [ABSTRACT FROM AUTHOR]

Circadian rhythms, as physiological systems with self‐regulatory functions in living organisms, are controlled by core clock genes and are involved in tumor development. The protein arginine methyltransferase 6 (PRMT6) serves as an oncogene in a myriad of solid tumors, including breast cancer. Hence, the primary aim of the current study is to investigate the molecular mechanisms by which the PRMT6 complex promotes breast cancer progression. The results show that PRMT6, poly(ADP‐ribose) polymerase 1 (PARP1), and the cullin 4 B (CUL4B)‐Ring E3 ligase (CRL4B) complex interact to form a transcription‐repressive complex that co‐occupies the core clock gene PER3 promoter. Moreover, genome‐wide analysis of PRMT6/PARP1/CUL4B targets identifies a cohort of genes that is principally involved in circadian rhythms. This transcriptional‐repression complex promotes the proliferation and metastasis of breast cancer by interfering with circadian rhythm oscillation. Meanwhile, the PARP1 inhibitor Olaparib enhances clock gene expression, thus, reducing breast carcinogenesis, indicating that PARP1 inhibitors have potential antitumor effects in high‐PRMT6 expression breast cancer. [ABSTRACT FROM AUTHOR]

Metabolic reprogramming is a hallmark of cancer, including lung cancer. However, the exact underlying mechanism and therapeutic potential are largely unknown. Here we report that protein arginine methyltransferase 6 (PRMT6) is highly expressed in lung cancer and is required for cell metabolism, tumorigenicity, and cisplatin response of lung cancer. PRMT6 regulated the oxidative pentose phosphate pathway (PPP) flux and glycolysis pathway in human lung cancer by increasing the activity of 6-phospho-gluconate dehydrogenase (6PGD) and α -enolase (ENO1). Furthermore, PRMT6 methylated R324 of 6PGD to enhancing its activity; while methylation at R9 and R372 of ENO1 promotes formation of active ENO1 dimers and 2-phosphoglycerate (2-PG) binding to ENO1, respectively. Lastly, targeting PRMT6 blocked the oxidative PPP flux, glycolysis pathway, and tumor growth, as well as enhanced the anti-tumor effects of cisplatin in lung cancer. Together, this study demonstrates that PRMT6 acts as a post-translational modification (PTM) regulator of glucose metabolism, which leads to the pathogenesis of lung cancer. It was proven that the PRMT6-6PGD/ENO1 regulatory axis is an important determinant of carcinogenesis and may become a promising cancer therapeutic strategy. PRMT6 promotes lung cancer growth and cisplatin response through enhancing oxidative pentose phosphate pathway flux and glycolysis pathway, which mediated by regulating the asymmetric arginine demethylation modification of 6PGD/ENO1. [Display omitted] [ABSTRACT FROM AUTHOR]

Protein arginine methyltransferase 6 (PRMT6) is a type I PRMT that is involved in epigenetic regulation of gene expression through methylating histone or non-histone proteins, and other processes such as alternative splicing, DNA repair, cell proliferation and senescence, and cell signaling. In addition, PRMT6 also plays different roles in various cancers via influencing cell growth, migration, invasion, apoptosis, and drug resistant, which make PRMT6 an anti-tumor therapeutic target for a variety of cancers. As a result, many PRMT6 inhibitors are being utilized to explore their efficacy as potential drugs for various cancers. In this review, we summarize the current knowledge on the function and structure of PRMT6. At the same time, we highlight the role of PRMT6 in different cancers, including the differentiation of its promotive or inhibitory effects and the underlying mechanisms. Apart from the above, current research progress and the potential mechanisms of PRMT6 behind them were also summarized. [ABSTRACT FROM AUTHOR]

Objective: Hair cells in the inner ear have been demonstrated to be sensitive to the ototoxicity from some beneficial pharmaceutical drugs. This study aimed to explore the role of protein arginine methyltransferase 6 (PRMT6) in the process of neomycin-induced hearing loss and the underlying mechanism. Methods: The neomycin-induced hearing loss mouse model and hair cell injury in vitro model were established. We took advantage of the HEI-OC1 cell line to evaluate PRMT6 expression in neomycin-induced hair cells, and the effect of PRMT6 on mitochondrial function and FoxG1 arginine methylation. Apoptotic cells were assessed and apoptotic marker cleaved caspase-3 level was detected. Reactive oxygen species (ROS) level and mitochondrial membrane potential (MMP) were subsequently measured. Result: The result showed that PRMT6 was significantly upregulated in neomycin-induced HEI-OC-1 cells, and PRMT6 silencing prevented MMP loss, reduced ROS production, as well as decreased cell apoptosis under neomycin treatment. Further results showed that FoxG1 was downregulated in neomycin-induced HEI-OC-1 cells, and PRMT6 promoted the FoxG1-mediated luciferase activity, while PRMT6 silencing reversed this effect. Mechanistic experiments revealed that PRMT6 silencing reduced the arginine methylation level of FoxG1 protein. In vivo, neomycin-induced upregulation of hearing thresholds and increased cell apoptosis, whereas PRMT6 inhibitor partly reversed these effects. Conclusion: Our findings suggested that inhibition of PRMT6 reduced neomycin-induced inner ear hair cell injury through the restraint of FoxG1 arginine methylation. [ABSTRACT FROM AUTHOR]

Protein arginine methyltransferase 6 (PRMT6) catalyses the asymmetric dimethylation of arginines on numerous substrate proteins within the human cell. In particular, PRMT6 methylates histone H3 arginine 2 (H3R2) which affects both gene repression and activation. However, the substrate specificity of PRMT6 has not been comprehensively analysed. Here, we systematically characterise the substrate recognition motif of PRMT6, finding that it has broad specificity and recognises the RG motif. Working with a H3 tail peptide as a template, on which we made 204 amino acid substitutions, we use targeted mass spectrometry to measure their effect on PRMT6 in vitro activity. We first show that PRMT6 methylates R2 and R8 in the H3 peptide, although H3R8 is methylated with lower efficiency and is not an in vivo PRMT6 substrate. We then quantify the effect of 194 of these amino acid substitutions on methylation at both H3R2 and H3R8. In both cases, we find that PRMT6 tolerates essentially any amino acid substitution in the H3 peptide, but that positively charged and bulky residues are preferred near the target arginine. We show that PRMT6 also has preference for glycine, but only in the position immediately following the target arginine. This indicates that PRMT6 recognises the RG motif rather than the RGG motif. We further confirm this preference for the RG motif on another PRMT6 substrate, histone H4R3. This broad specificity and recognition of RG rather than RGG are distinctive among the PRMT family and has implications for the development of drugs to selectively target PRMT6. Databases: Panorama Public (https://panoramaweb.org/PRMT6motif.url); ProteomeXchange (PXD016711). [ABSTRACT FROM AUTHOR]

[Display omitted] • A series of novel adamantane hydrophobic tags derivatives have been designed and synthesized. • SKLB0124 was developed as the first-in-class degrader for PRMT6. • SKLB-0124 selectively degraded PRMT6 over PRMT1/8. • SKLB-0124 showed significant antiproliferative activities. PRMT6 is a member of the protein arginine methyltransferase family, which participates in a variety of physical processes and plays an important role in the occurrence and development of tumors. Using small molecules to design and synthesize targeted protein degraders is a new strategy for drug development. Here, we report the first-in-class degrader SKLB-0124 for PRMT6 based on the hydrophobic tagging (HyT) method. Importantly, SKLB-0124 induced proteasome dependent degradation of PRMT6 and significantly inhibited the proliferation of HCC827 and MDA-MB-435 cells. Moreover, SKLB-0124 effectively induced apoptosis and cell cycle arrest in these two cell lines. Our data clarified that SKLB-0124 is a promising selective PRMT6 degrader for cancer therapy which is worthy of further evaluation. [ABSTRACT FROM AUTHOR]

Protein arginine methylation is a prevalent posttranslational modification and protein arginine methyltransferases 6 (PRMT6) has been identified as a suppressor of TBK1/IRF3 in human and mammals. To explore the role of PRMT6 in teleost fish, PRMT6 homologue of black carp (Mylopharyngodon piceus) has been cloned and characterized in this study. Black carp PRMT6 (bcPRMT6) transcription in host cells varies in response to different stimuli and bcPRMT6 migrates around 43 kDa in the immunoblot assay. Like its mammalian counterpart, bcPRMT6 has been identified to distribute majorly in the nucleus through the immunofluorescent staining assay. bcPRMT6 shows little interferon (IFN) promoter-inducing activity in the reporter assay and bcPRMT6 shows no antiviral activity against either grass carp reovirus (GCRV) or spring viremia of carp virus (SVCV) in plaque assay. When co-expressed with bcPRMT6, the IFN promoter-inducing abilities of black carp TBK1 (bcTBK1) and IRF3/7 (bcIRF3/7) are fiercely attenuated. Accordingly, bcTBK1-mediated antiviral activity in EPC cells is obviously dampened by bcPRMT6. The interaction between bcPRMT6 and bcIRF3/7 has been identified by co-immunoprecipitation assay; however, no direct association between bcPRMT6 and bcTBK1 has been detected. Taken together, our data elucidates for the first time in teleost fish that PRMT6 suppresses TBK1-IRF3/7 signaling during host antiviral innate immune activation. • bcPRMT6 suppresses bcTBK1 and bcIRF3/7 mediated IFN production. • bcPRMT6 inhibits bcTBK1 mediated antiviral activity. • bcPRMT6 interacts with bcIRF3/7, but not with bcTBK1. [ABSTRACT FROM AUTHOR]

PRMT6 is a member of the protein arginine methyltransferase family, which is involved in a variety of physiological processes and plays an important role in the occurrence and development of tumors. Due to the high homology of type Ⅰ PRMTs and the two close binding sites of the SAM pocket and the substrate pocket, selective PRMT6 inhibitors have rarely been reported. In this study, a series of (5-phenylpyridin-3-yl)methanamine derivatives were designed and synthesized, which could form hydrogen bonding interactions with the unique Glu49 of PRMT6, thereby improving the selectivity of the compounds for PRMT6. Among them, a25 had the best activity and selectivity, with more than 25-fold selectivity for PRMT1/8 and more than 50-fold selectivity for PRMT3/4/5/7, which was superior to these reported SAM competitive and substrate competitive PRMT6 inhibitors. Importantly, a25 could significantly inhibit the proliferation of various tumor cells and effectively induce apoptosis of cancer cells. Our data clarified that a25 is a promising selective PRMT6 inhibitor for cancer therapy which is worthy of further evaluation. [Display omitted] • A series of novel and selective PRMT6 inhibitors have been synthesized. • a25 was 30-fold selective for PRMT1 and 28-fold selective for PRMT8. • a25 significantly inhibit the proliferation of various tumor cells. • a25 showed reasonable pharmacokinetic profile. [ABSTRACT FROM AUTHOR]

Protein arginine methyltransferases (PRMT6) has been shown to negatively regulate interferon (IFN) production in mammals, however, the role of teleost PRMT6 in IFN signaling remains largely unknown. In our previous study, black carp (Mylopharyngodon piceus) PRMT6 (bcPRMT6) has been identified to inhibit bcTBK1/bcIRF3 cascade. In this study, bcIRF3-induced transcription of bcIFNa, bcIFNb, bcp50 and bcIl1β in host cells was attenuated by co-expressed bcPRMT6. Accordingly, bcIRF3-mediated antiviral activity against grass carp reovirus (GCRV) and spring viremia of carp virus (SVCV) was obviously dampened by bcPRMT6. Knockdown of bcPRMT6 enhanced the antiviral ability of host cells and improved the transcription of bcIFNa, bcViperin and bcIl1β. When co-expressed with bcPRMT6 in either mammalian or fish cells, the protein level of bcIRF3 was decreased, which implied the triggered degradation of bcIRF3 by bcPRMT6. And interestingly, this decreased protein expression of bcIRF3 was rescued by chloroquine but not MG132, indicating the lysosome-dependent degradation of this molecule. The subsequent immunoprecipitation and immunoblot assay demonstrated that K63-linked ubiquitination but not K48-linked of bcIRF3 was obviously attenuated by bcPRMT6. And the immunofluorescent staining data suggested that the nuclear translocation of bcIRF3 was inhibited by bcPRMT6. Taken together, our data concludes that bcPRMT6 promotes the degradation of bcIRF3 through lysosome pathway and inhibits K63-linked ubiquitination of bcIRF3, leading to the dampened antiviral signaling mediated by bcIRF3. • Black carp PRMT6 promotes lysosome-dependent degradation of black carp IRF3. • Back carp PRMT6 dampens IRF3-mediated antiviral signaling. • Black carp PRMT6 inhibits K63-linked ubiquitination of black carp IRF3. [ABSTRACT FROM AUTHOR]

Protein arginine methyltransferase 6 (PRMT6) is a type I arginine methyltransferase that asymmetrically dimethylates histone H3 arginine 2 (H3R2me2a). However, the biological roles and underlying molecular mechanisms of PRMT6 in colorectal cancer (CRC) remain unclear. PRMT6 expression in CRC tissue was examined using immunohistochemistry. The effect of PRMT6 on CRC cells was investigated in vitro and in vivo. Mass spectrometry, co-immunoprecipitation and GST pulldown assays were performed to identify interaction partners of PRMT6. RNA-seq, chromatin immunoprecipitation, Western blot and qRT-PCR assays were used to investigate the mechanism of PRMT6 in gene regulation. PRMT6 is significantly upregulated in CRC tissues and facilitates cell proliferation of CRC cells in vitro and in vivo. Through RNA-seq analysis, CDKN2B (p15INK4b) and CCNG1 were identified as new transcriptional targets of PRMT6. PRMT6-dependent H3R2me2a mark was predominantly deposited at the promoters of CDKN2B and CCNG1 in CRC cells. Furthermore, PRMT5 was firstly characterized as an interaction partner of PRMT6. Notably, H3R2me2a coincides with PRMT5-mediated H4R3me2s and H3R8me2s marks at the promoters of CDKN2B and CCNG1 genes, thus leading to transcriptional repression of these genes. PRMT6 functionally associates with PRMT5 to promote CRC progression through epigenetically repressing the expression of CDKN2B and CCNG1. These insights raise the possibility that combinational intervention of PRMT6 and PRMT5 may be a promising strategy for CRC therapy. [ABSTRACT FROM AUTHOR]

Androgens and the androgen receptor (AR) are of great importance to spermatogenesis and male fertility. AR knockout (ARKO) mice display a complete insensitivity to androgens and male infertility; however, the exact molecular mechanism for this effect remains unclear. In this study, we found that the expression levels of Prmt6 mRNA and protein were significantly up-regulated in the testes of ARKO mice compared to wild type (WT) mice. PRMT6 was principally localized to the nucleus of spermatogonia and spermatocytes by immunofluorescence staining. Furthermore, luciferase assay data showed that AR together with testosterone treatment suppressed Prmt6 transcription via binding to the androgen-responsive element (ARE) of the Prmt6 promoter. Moreover, knockdown of Prmt6 suppressed germ cells migration and promoted apoptosis. In addition, both of these cellular activities could not be enhanced by testosterone treatment. Taken together, these data indicate that PRMT6, which was down-regulated by AR and influenced cell migration and apoptosis of germ cells, could play a potentially important role in spermatogenesis. [ABSTRACT FROM AUTHOR]

PRMT6 is a protein arginine methyltransferase involved in transcriptional regulation, human immunodeficiency virus pathogenesis, DNA base excision repair, and cell cycle progression. Like other PRMTs, PRMT6 is overexpressed in several cancer types and is therefore considered as a potential anti-cancer drug target. In the present study, we described six crystal structures of PRMT6 from Mus musculus , solved and refined at 1.34 Å for the highest resolution structure. The crystal structures revealed that the folding of the helix αX is required to stabilize a productive active site before methylation of the bound peptide can occur. In the absence of cofactor, metal cations can be found in the catalytic pocket at the expected position of the guanidinium moiety of the target arginine substrate. Using mass spectrometry under native conditions, we show that PRMT6 dimer binds two cofactor and a single H4 peptide molecules. Finally, we characterized a new site of in vitro automethylation of mouse PRMT6 at position 7. [ABSTRACT FROM AUTHOR]

Highlights: [•] An evolutionarily conserved AT-hook motif is present in the MHCII regulator RFX5. [•] The AT-hook motif is necessary for proper HLA-DQ, but not HLA-DR expression. [•] Defective expression of HLA-DQ is due to defective transcription of the HLA-DQA chain. [•] PRMT6 methylates the AT-hook and downregulates HLA-DQ expression. [ABSTRACT FROM AUTHOR]

Background: Protein arginine methyltransferase 6 (PRMT6) is a nuclear enzyme that methylates arginine residues on histones and transcription factors. In addition, PRMT6 inhibits HIV-1 replication in cell culture by directly methylating and interfering with the functions of several HIV-1 proteins, i.e. Tat, Rev and nucleocapsid (NC). PRMT6 also displays automethylation capacity but the role of this post-translational modification in its antiretroviral activity remains unknown. Results: Here we report the identification by liquid chromatography-mass spectrometry of R35 within PRMT6 as the target residue for automethylation and have confirmed this by site-directed mutagenesis and in vitro and in vivo methylation assays. We further show that automethylation at position 35 greatly affects PRMT6 stability and is indispensable for its antiretroviral activity, as demonstrated in HIV-1 single-cycle TZM-bl infectivity assays. Conclusion: These results show that PRMT6 automethylation plays a role in the stability of this protein and that this event is indispensible for its anti-HIV-1 activity. [ABSTRACT FROM AUTHOR]

Abstract: In this study, we investigate the molecular mechanism by which protein arginine methyltransferase 6 (PRMT6) exerts anti-invasiveness effect against breast cancer cells and prostate cancer cells. PRMT6 has been known to be responsible for asymmetric dimethylation of histone H3 at R2 (H3R2me2a). To investigate the biological role of PRMT6, we first established stable cell lines expressing GFP-PRMT6 with MCF7 and PC3 cells. Growth rates and colony forming abilities of PRMT6-overexpressing cells were significantly retarded compared to control GFP expressing cells. This growth retardation seems to be associated with p21WAF1 induction. In addition, our data show that migration and invasion of prostate cancer cells was strongly suppressed by PRMT6 overexpression. In parallel, the levels of thrombospondin-1 (TSP-1), a potent natural inhibitor of angiogenesis, were highly up-regulated in both PRMT6-overexpressing cells. Furthermore, this suppression of migration and invasion by PRMT6 overexpression was significantly rescued by specific knock-down of TSP-1. Concomitantly, down-regulations of MMP-2 and -9 were observed in PRMT6-overexpressing cells. Taken together, our data demonstrate that PRMT6 overexpression is associated with regulation of motility and invasion through up-regulation of TSP-1 and down-regulation of MMPs in human cancer cells. [Copyright &y& Elsevier]

Abstract: The tumor suppressor p16 INK4A (p16) blocks the cell cycle progression by inhibiting phosphorylation of the retinoblastoma protein. We describe here a novel aspect of the posttranslational control that has an important functional consequence on p16 protein. We first discovered that the p16 protein was methylated in various cell lineages. We then determined that the arginine 22, 131 and 138 of p16 were the main methylation sites. Western blotting and TUNEL analyses revealed that the p16 protein bearing these point mutations induced a higher apoptosis ratio than wild-type p16 in A549 cells. Furthermore, co-immunoprecipitation assays suggested that decrease of p16 arginine methylation level promoted the association of p16 with CDK4. Additionally, we determined that the protein arginine methyltransferase 6 (PRMT6) was responsible for the p16 arginine methylation. Results from flow cytometric analysis demonstrated that PRMT6 overexpression counteracted the cell cycle arrest at G1 phase induced by wild-type p16 in A549 cells. We also provided evidence that PRMT6 was able to interact with p16, and that the intensity of p16-CDK4 association was reduced upon PRMT6 overexpression. Together, data presented in this report establish that methylation at specific arginine residues of p16 protein by PRMT6 may be critical for the activity of p16. [Copyright &y& Elsevier]

Subcellular localization analysis implicated that CiPRMT6 was mainly located in the nucleus, with a small part of them located in the cytoplasm. PRMT6, namely protein arginine methyltransferase 6, was first identified and demonstrated to catalyze the methylation of arginine residue on the chromatin histones in mammals. Mammalian PRMT6 usually acts as an arginine methyltransferase in the nucleus, but induces antiviral innate immune response in the cytoplasm. Nowadays, there have been few reports about PRMT6 in teleost. In this study, we investigated the potential molecular mechanisms underlying the interaction of PRMT6 expression and IFN1 response in grass carp. We first cloned and identified a grass carp PRMT6 (named CiPRMT6, MN781672.1), which is 1068bp in length encoding a deduced polypeptide of 355 amino acids. In CIK cell, CiPRMT6 expression was up-regulated upon stimulation with poly (I:C); while overexpression of PRMT6 suppressed the promoter activity of grass carp IFN1 and reduced the phosphorylation of IRF3; however, the amount of PRMT6 mutant (lack of methyltransferase domain) was increased in the cytoplasm. Our results also showed that grass carp PRMT6 and IRF3 (but not TBK1) were co-located and bound to each other in the cytoplasm. The binding of CiPRMT6 to IRF3 impairs the interaction between TBK1 and IRF3, indicating that CiPRMT6 is a negative regulator for IFN1 expression through TBK1-IRF3 signaling pathway in grass carp. In conclusion, we identified that CiPRMT6 negatively regulated IFN1 expression by inhibiting the TBK1-IRF3 interaction as well as IRF3 phosphorylation. • Grass carp PRMT6 can be upregulated by poly I:C. • Grass carp PRMT6 reduces the phosphorylation level of IRF3. • The binding of grass carp PRMT6 to IRF3 impairs grass carp TBK1/IRF3 binding. • Grass carp PRMT6 reduces IFN1 expression by blocking TBK1-IRF3. [ABSTRACT FROM AUTHOR]

Members of the protein arginine methyltransferase (PRMT) family methylate the arginine residue(s) of several proteins and regulate a broad spectrum of cellular functions. Protein arginine methyltransferase 6 (PRMT6) is a type I PRMT that asymmetrically dimethylates the arginine residues of numerous substrate proteins. PRMT6 introduces asymmetric dimethylation modification in the histone 3 at arginine 2 (H3R2me2a) and facilitates epigenetic regulation of global gene expression. In addition to histones, PRMT6 methylates a wide range of cellular proteins and regulates their functions. Here, we discuss (i) the biochemical aspects of enzyme kinetics, (ii) the structural features of PRMT6 and (iii) the diverse functional outcomes of PRMT6 mediated arginine methylation. Finally, we highlight how dysregulation of PRMT6 is implicated in various types of cancers and response to viral infections. [ABSTRACT FROM AUTHOR]

Ovarian cancer is one of the leading causes of mortality in women worldwide. Currently, paclitaxel is one of the most effective chemotherapies. However, resistance to paclitaxel is a major cause of therapy failure and the precise mechanism of paclitaxel resistance remains unclear. In this study, we demonstrated that the oxidative pentose phosphate pathway (PPP) enzyme glucose-6-phosphate dehydrogenase (G6PD) promotes paclitaxel resistance. We showed that G6PD expression was higher in paclitaxel-resistant cancer cells than in their paclitaxel-sensitive counterparts. Furthermore, we demonstrated that suppressing G6PD using shRNA, or an inhibitor, either as single agents or in combination, sensitized paclitaxel-resistant cancer cells to paclitaxel treatment and thereby improving the therapeutic efficacy of paclitaxel. Interestingly, we found that the upregulation of G6PD in paclitaxel-resistant cells was due to the decreased expression of protein arginine methyltransferase 6 (PRMT6), which targets the promoter of G6PD. We further identified that G6PD promotes paclitaxel resistance by regulating the expression of glutathione S-transferase P1 (GSTP1), which confers resistance to chemotherapy by detoxifying several anticancer drugs. Taken together, our results suggest that G6PD is a novel potential target to overcome paclitaxel resistance. [ABSTRACT FROM AUTHOR]

• PRMT6 expression is upregulated in EMC and correlated with poor outcomes in two independent cohorts of 564 patients. • PRMT6 is targeted and downregulated by miR-372-3p in EMC cells. • PRMT6 promotes EMC cell proliferation and migration. • PRMT6 exerts oncogenic effects via activation of AKT/mTOR pathway. Arginine methylation plays essential roles in post-transcriptional modification and signal transduction. Dysregulation of protein arginine methyltransferases (PRMTs) has been reported in human cancers, yet the expression and biological function of PRMT6 in endometrial cancer (EMC) remains unclear. Here, we show that PRMT6 is upregulated in EMC and exhibits oncogenic activities via activation of AKT/mTOR pathway. The expression of PRMT6 in EMC is much higher than that in the adjacent nontumorous tissues. Elevated PRMT6 expression is significantly associated with higher histological tumor grade and unfavorable prognosis in two independent cohorts consisting of a total of 564 patients with EMC. In vitro data demonstrate that PRMT6 expression was identified as a downstream target of miR-372-3p. Ectopic expression of miR-372-3p downregulates PRMT6. Overexpression of PRMT6 promotes EMC cell proliferation and migration, whereas knockdown of PRMT6 leads to opposite phenotypes. Mechanistically, PRMT6 induces the phosphorylation of AKT and mTOR in EMC cells. Inhibition of AKT/mTOR signaling by MK2206 or rapamycin attenuates the PRMT6-mediated EMC progression. In clinical samples, high expression of PRMT6 was correlated to low expression of miR-372-3p and high expression of phosphorylated AKT. Collectively, our findings suggest PRMT6 may function as an oncogene to promote tumor progression, and be of prognostic value to predict disease-free survival of patients with EMC. The newly identified miR-372-3p/PRMT6/AKT/mTOR axis represents a new promising target for EMC management. [ABSTRACT FROM AUTHOR]