RESUMO
BACKGROUND: Diabetic nephropathy (DN) is a common complication of diabetes mellitus, and Prolyl 4-Hydroxylase Subunit Beta (P4HB) expression is increased in high glucose (HG)-induced renal tubular epithelial cells (TECs). But it's role in HG-induced TECs remains to be elucidated. METHODS: The HK-2 cells were induced using HG and transfected with SiRNA-P4HB. DCFH-DA staining was utilized for the detection of cellular levels of ROS. WB and immunofluorescence were utilized to detect the expression of P4HB, epithelial-mesenchymal transition (EMT), fibrosis, and TGFß/SMAD3-related proteins in HK-2 cells. Online databases were utilized for predicting the interaction target of P4HB, and immunoprecipitation (IP) experiments were employed to validate the binding of P4HB with the target. SiRNA and overexpression vectors of target gene were used to verify the mechanism of action of P4HB. RESULTS: HG induced an increase in the expression of P4HB and TGFß, p-SMAD3, and ROS in HK-2 cells. Furthermore, HG downregulated the expression of E-cadherin and upregulated the expression of N-cadherin, Vimentin, α-SMA, Fibronectin, Collagen IV, SNAIL, and SLUG in HK-2 cells. Interfering with P4HB significantly reversed the expression of these proteins. Database predictions and IP experiments showed that P4HB interacts with PRMT1, and the expression of PRMT1 was increased in HG-induced HK-2 cells. Interfering with PRMT1 inhibited the changes in expression of EMT and fibrosis related proteins induced by HG. However, overexpression of PRMT1 weakened the regulatory effect of P4HB interference on the EMT, fibrosis, and TGFß/SMAD3-related proteins in HK-2 cells. CONCLUSION: P4HB regulated the TGFß/SMAD3 signaling pathway through PRMT1 and thus participates in HG-induced EMT and fibrosis in HK-2 cells.
Assuntos
Células Epiteliais , Transição Epitelial-Mesenquimal , Fibrose , Glucose , Túbulos Renais , Proteína-Arginina N-Metiltransferases , Proteínas Repressoras , Transdução de Sinais , Proteína Smad3 , Fator de Crescimento Transformador beta , Humanos , Proteína Smad3/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Glucose/farmacologia , Glucose/toxicidade , Glucose/metabolismo , Proteína-Arginina N-Metiltransferases/metabolismo , Proteína-Arginina N-Metiltransferases/genética , Fator de Crescimento Transformador beta/metabolismo , Túbulos Renais/patologia , Túbulos Renais/metabolismo , Proteínas Repressoras/metabolismo , Proteínas Repressoras/genética , Linhagem Celular , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
Cancer cells autonomously alter metabolic pathways in response to dynamic nutrient conditions in the microenvironment to maintain cell survival and proliferation. A better understanding of these adaptive alterations may reveal the vulnerabilities of cancer cells. Here, we demonstrate that coactivator-associated arginine methyltransferase 1 (CARM1) is frequently overexpressed in gastric cancer and predicts poor prognosis of patients with this cancer. Gastric cancer cells sense a reduced extracellular glucose content, leading to activation of nuclear factor erythroid 2-related factor 2 (NRF2). Subsequently, NRF2 mediates the classic antioxidant pathway to eliminate the accumulation of reactive oxygen species induced by low glucose. We found that NRF2 binds to the CARM1 promoter, upregulating its expression and triggering CARM1-mediated hypermethylation of histone H3 methylated at R arginine 17 (H3R17me2) in the glucose-6-phosphate dehydrogenase gene body. The upregulation of this dehydrogenase, driven by the H3R17me2 modification, redirects glucose carbon flux toward the pentose phosphate pathway. This redirection contributes to nucleotide synthesis (yielding nucleotide precursors, such as ribose-5-phosphate) and redox homeostasis and ultimately facilitates cancer cell survival and growth. NRF2 or CARM1 knockdown results in decreased H3R17me2a accompanied by the reduction of glucose-6-phosphate dehydrogenase under low glucose conditions. Collectively, this study reveals a significant role of CARM1 in regulating the tumor metabolic switch and identifies CARM1 as a potential therapeutic target for gastric cancer treatment.
Assuntos
Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Glucose , Fator 2 Relacionado a NF-E2 , Via de Pentose Fosfato , Proteína-Arginina N-Metiltransferases , Neoplasias Gástricas , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Humanos , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Via de Pentose Fosfato/genética , Glucose/metabolismo , Proteína-Arginina N-Metiltransferases/metabolismo , Proteína-Arginina N-Metiltransferases/genética , Linhagem Celular Tumoral , Animais , Glucosefosfato Desidrogenase/metabolismo , Glucosefosfato Desidrogenase/genética , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Histonas/metabolismo , Regiões Promotoras Genéticas/genética , Camundongos Nus , Transcrição Gênica , Proliferação de Células/genéticaRESUMO
In addition to the ubiquitous loss of the VHL gene in clear cell renal cell carcinoma (ccRCC), co-deletions of chromatin-regulating genes are common drivers of tumorigenesis, suggesting potential vulnerability to epigenetic manipulation. A library of chemical probes targeting a spectrum of epigenetic regulators is screened using a panel of ccRCC models. MS023, a type I protein arginine methyltransferase (PRMT) inhibitor, is identified as an antitumorigenic agent. Individual knockdowns indicate PRMT1 as the specific critical dependency for cancer growth. Further analyses demonstrate impairments to cell cycle and DNA damage repair pathways upon MS023 treatment or PRMT1 knockdown. PRMT1-specific proteomics reveals an interactome rich in RNA binding proteins and further investigation indicates significant widespread disruptions in mRNA metabolism with both MS023 treatment and PRMT1 knockdown, resulting in R-loop accumulation and DNA damage over time. Our data supports PRMT1 as a target in ccRCC and informs a mechanism-based strategy for translational development.
Assuntos
Carcinoma de Células Renais , Dano ao DNA , Neoplasias Renais , Proteína-Arginina N-Metiltransferases , Proteínas Repressoras , Animais , Humanos , Camundongos , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Proteína-Arginina N-Metiltransferases/metabolismo , Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Proteína-Arginina N-Metiltransferases/genética , Proteômica , Proteínas Repressoras/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/antagonistas & inibidores , RNA/metabolismo , RNA/genética , MasculinoRESUMO
BACKGROUND: Hyperactivated protein arginine methyltransferases (PRMTs) are implicated in human cancers. Inhibiting tumor intrinsic PRMT5 was reported to potentiate antitumor immune responses, highlighting the possibility of combining PRMT5 inhibitors (PRMT5i) with cancer immunotherapy. However, global suppression of PRMT5 activity impairs the effector functions of immune cells. Here, we sought to identify strategies to specifically inhibit PRMT5 activity in tumor tissues and develop effective PRMT5i-based immuno-oncology (IO) combinations for cancer treatment, particularly for methylthioadenosine phosphorylase (MTAP)-loss cancer. METHODS: Isogeneic tumor lines with and without MTAP loss were generated by CRISPR/Cas9 knockout. The effects of two PRMT5 inhibitors (GSK3326595 and MRTX1719) were evaluated in these isogenic tumor lines and T cells in vitro and in vivo. Transcriptomic and proteomic changes in tumors and T cells were characterized in response to PRMT5i treatment. Furthermore, the efficacy of MRTX1719 in combination with immune checkpoint blockade was assessed in two syngeneic murine models with MTAP-loss tumor. RESULTS: GSK3326595 significantly suppresses PRMT5 activity in tumors and T cells regardless of the MTAP status. However, MRTX1719, a methylthioadenosine-cooperative PRMT5 inhibitor, exhibits tumor-specific PRMT5 inhibition in MTAP-loss tumors with limited immunosuppressive effects. Mechanistically, transcriptomic and proteomic profiling analysis reveals that MRTX1719 successfully reduces the activation of the PI3K pathway, a well-documented immune-resistant pathway. It highlights the potential of MRTX1719 to overcome immune resistance in MTAP-loss tumors. In addition, MRTX1719 sensitizes MTAP-loss tumor cells to the killing of tumor-reactive T cells. Combining MRTX1719 and anti-PD-1 leads to superior antitumor activity in mice bearing MTAP-loss tumors. CONCLUSION: Collectively, our results provide a strong rationale and mechanistic insights for the clinical development of MRTX1719-based IO combinations in MTAP-loss tumors.
Assuntos
Proteína-Arginina N-Metiltransferases , Purina-Núcleosídeo Fosforilase , Animais , Camundongos , Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Proteína-Arginina N-Metiltransferases/metabolismo , Humanos , Purina-Núcleosídeo Fosforilase/antagonistas & inibidores , Purina-Núcleosídeo Fosforilase/metabolismo , Linfócitos T/imunologia , Linfócitos T/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Isoquinolinas , PirimidinasRESUMO
The African clawed frog (Xenopus laevis) endures prolonged periods of dehydration while estivating underground during the dry season. Epigenetic modifications play crucial roles in regulating gene expression in response to environmental changes. The elucidation of epigenetic changes relevant to survival could serve as a basis for further studies on organ preservation under extreme stress. The current study examined the relative protein levels of key enzymes involved in the arginine methylation of histones in the liver and kidney tissues of control versus dehydrated (35 ± 1%) X. laevis through immunoblotting. Protein arginine methyltransferases (PRMT) 4, 5, and 6 showed significant protein level decreases of 35 ± 3%, 71 ± 7%, and 25 ± 5%, respectively, in the liver tissues of the dehydrated frogs relative to controls. In contrast, PRMT7 exhibited an increase of 36 ± 4%. Similarly, the methylated histone markers H3R2m2a, H3R8m2a, and H3R8m2s were downregulated by 34 ± 11%, 15 ± 4%, and 42 ± 12%, respectively, in the livers of dehydrated frogs compared to controls. By contrast, the kidneys of dehydrated frogs showed an upregulation of histone markers. H3R2m2a, H3R8m2a, H3R8m2s, and H4R3m2a were significantly increased by 126 ± 12%, 112 ± 7%, 47 ± 13%, and 13 ± 3%, respectively. These changes can play vital roles in the metabolic reorganization of X. laevis during dehydration, and are likely to increase the chances of survival. In turn, the tissue-specific regulation of the histone arginine methylation mechanism suggests the importance of epigenetic regulation in the adaptation of X. laevis for whole-body dehydration.
Assuntos
Arginina , Histonas , Fígado , Xenopus laevis , Animais , Xenopus laevis/genética , Histonas/metabolismo , Histonas/genética , Metilação , Arginina/metabolismo , Fígado/metabolismo , Desidratação/genética , Desidratação/metabolismo , Proteína-Arginina N-Metiltransferases/genética , Proteína-Arginina N-Metiltransferases/metabolismo , Epigênese Genética , Rim/metabolismo , Regulação da Expressão Gênica , Proteínas de Xenopus/genética , Proteínas de Xenopus/metabolismoRESUMO
Protein arginine N-methyltransferases (PRMT) are a family of S-adenosyl-l-methionine (SAM)-dependent enzymes that transfer methyl-groups to the ω-N of arginyl residues in proteins. PRMTs are involved in regulating gene expression, RNA splicing, and other activities. PRMT1 is responsible for most cellular arginine methylation, and its dysregulation is involved in many cancers. Accordingly, many groups have targeted PRMT1 using small molecules and peptide inhibitors. In this Perspective, we discuss the structure and function of selected peptide and small molecule inhibitors of PRMT1. We examine inhibitors that target the substrate arginyl peptide, SAM, or both binding sites, and the type of inhibition that results. Small molecules, and peptides that are bisubstrate, and/or PRMT transition state mimic inhibitors as well as inhibitors that alkylate PRMTs will be discussed. We define a structure-activity relationship for the aromatic/heteroaromatic N-methylethylenediamine inhibitors of PRMT1 and review current progress of PRMT1 inhibitors in clinical trials.
Assuntos
Inibidores Enzimáticos , Peptídeos , Proteína-Arginina N-Metiltransferases , Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Proteína-Arginina N-Metiltransferases/metabolismo , Proteína-Arginina N-Metiltransferases/química , Humanos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Relação Estrutura-Atividade , Peptídeos/química , Peptídeos/farmacologia , Peptídeos/síntese química , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Proteínas RepressorasRESUMO
CARM1 is predominantly localized in the nucleus and plays a pivotal role in maintaining mitochondrial homeostasis by regulating gene expression. It suppresses mitochondrial biogenesis by downregulating PGC-1α and TFAM expression, while promoting mitochondrial fission through increased DNM1L expression. Under oxidative stress, CARM1 translocates to the cytoplasm, where it directly methylates DRP1 and accelerates mitochondrial fission, enhancing reactive oxygen species (ROS) production. Cytoplasmic localization of CARM1 is facilitated by its phosphorylation at S595 by ROS-activated p38γ MAPK, creating a positive feedback loop. Consequently, cytoplasmic CARM1 contributes to cellular senescence by altering mitochondrial dynamics and increasing ROS levels. This observation was supported by the increased cytoplasmic CARM1 levels and disrupted mitochondrial dynamics in the transformed 10T1/2 cells. Moreover, CARM1 inhibitors not only inhibit the proliferation of cancer cells but also induce apoptotic death in senescent cells. These findings highlight the potential of CARM1 inhibitors, particularly those targeting cytoplasmic functions, as novel strategies for eliminating cancer and senescent cells.
Assuntos
Senescência Celular , Proteína-Arginina N-Metiltransferases , Espécies Reativas de Oxigênio , Espécies Reativas de Oxigênio/metabolismo , Humanos , Fosforilação , Proteína-Arginina N-Metiltransferases/metabolismo , Proteína-Arginina N-Metiltransferases/genética , Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Dinâmica Mitocondrial , Mitocôndrias/metabolismo , Citoplasma/metabolismo , Estresse Oxidativo , Apoptose , Proliferação de Células , CamundongosRESUMO
Epigenetic readers frequently affect gene regulation, correlate with disease prognosis, and hold significant potential as therapeutic targets for cancer. Zinc finger MYND-type containing 11 (ZMYND11) is notably recognized for reading the epigenetic marker H3.3K36me3; however, its broader functions and mechanisms of action in cancer remain underexplored. Here, we report that ZMYND11 downregulation is prevalent across various cancers and profoundly correlates with poorer outcomes in prostate cancer patients. Depletion of ZMYND11 promotes tumor cell growth, migration, and invasion in vitro, as well as tumor formation and metastasis in vivo. Mechanistically, we discover that ZMYND11 exhibits tumor suppressive roles by recognizing arginine-194-methylated HNRNPA1 dependent on its MYND domain, thereby retaining HNRNPA1 in the nucleus and preventing the formation of stress granules in the cytoplasm. Furthermore, ZMYND11 counteracts the HNRNPA1-driven increase in the PKM2/PKM1 ratio, thus mitigating the aggressive tumor phenotype promoted by PKM2. Remarkably, ZMYND11 recognition of HNRNPA1 can be disrupted by pharmaceutical inhibition of the arginine methyltransferase PRMT5. Tumors with low ZMYND11 expression show sensitivity to PRMT5 inhibitors. Taken together, our findings uncover a previously unexplored noncanonical role of ZMYND11 as a nonhistone methylation reader and underscore the critical importance of arginine methylation in the ZMYND11-HNRNPA1 interaction for restraining tumor progression, thereby proposing novel therapeutic targets and potential biomarkers for cancer treatment.
Assuntos
Epigênese Genética , Ribonucleoproteína Nuclear Heterogênea A1 , Humanos , Ribonucleoproteína Nuclear Heterogênea A1/genética , Ribonucleoproteína Nuclear Heterogênea A1/metabolismo , Epigênese Genética/genética , Masculino , Grânulos de Estresse/genética , Grânulos de Estresse/metabolismo , Linhagem Celular Tumoral , Camundongos , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Neoplasias da Próstata/metabolismo , Proteína-Arginina N-Metiltransferases/genética , Proteína-Arginina N-Metiltransferases/metabolismo , Animais , Regulação Neoplásica da Expressão Gênica/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Carcinogênese/genética , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Proteínas de Ligação a DNA , Proteínas de Ciclo Celular , Proteínas CorrepressorasRESUMO
Kaposi's sarcoma-associated herpesvirus (KSHV) is a double-stranded DNA virus that encodes numerous cellular homologs, including cyclin D, G protein-coupled protein, interleukin-6, and macrophage inflammatory proteins 1 and 2. KSHV vCyclin encoded by ORF72, is the homolog of cellular cyclinD2. KSHV vCyclin can regulate virus replication and cell proliferation by constitutively activating cellular cyclin-dependent kinase 6 (CDK6). However, the regulatory mechanism of KSHV vCyclin has not been fully elucidated. In the present study, we identified a host protein named protein arginine methyltransferase 5 (PRMT5) that interacts with KSHV vCyclin. We further demonstrated that PRMT5 is upregulated by latency-associated nuclear antigen (LANA) through transcriptional activation. Remarkably, knockdown or pharmaceutical inhibition (using EPZ015666) of PRMT5 inhibited the cell cycle progression and cell proliferation of KSHV latently infected tumor cells. Mechanistically, PRMT5 methylates vCyclin symmetrically at arginine 128 and stabilizes vCyclin in a methyltransferase activity-dependent manner. We also show that the methylation of vCyclin by PRMT5 positively regulates the phosphorylate retinoblastoma protein (pRB) pathway. Taken together, our findings reveal an important regulatory effect of PRMT5 on vCyclin that facilitates cell cycle progression and proliferation, which provides a potential therapeutic target for KSHV-associated malignancies.
Assuntos
Ciclo Celular , Proliferação de Células , Herpesvirus Humano 8 , Proteína-Arginina N-Metiltransferases , Proteína-Arginina N-Metiltransferases/metabolismo , Proteína-Arginina N-Metiltransferases/genética , Humanos , Herpesvirus Humano 8/metabolismo , Herpesvirus Humano 8/fisiologia , Metilação , Antígenos Virais/metabolismo , Antígenos Virais/genética , Proteínas Virais/metabolismo , Proteínas Virais/genética , Ciclina D2/metabolismo , Células HEK293 , Replicação Viral/fisiologia , Sarcoma de Kaposi/virologia , Sarcoma de Kaposi/metabolismo , Proteínas NuclearesRESUMO
Protein arginine methylation is a common post-translational modification (PTM) catalyzed by nine protein arginine methyltransferases (PRMTs). As the major symmetric arginine methyltransferase that methylates both histone and non-histone substrates, PRMT5 plays key roles in a number of biological processes critical for development and tumorigenesis. PRMT5 overexpression has been reported in multiple cancer types including prostate cancer (PCa), but the exact biological and mechanistic understanding of PRMT5 in aggressive PCa remains ill-defined. Here, we show that PRMT5 is upregulated in PCa, correlates with worse patient survival, promotes corrupted RNA splicing, and functionally cooperates with an array of pro-tumorigenic pathways to enhance oncogenesis. PRMT5 inhibition via either genetic knockdown or pharmacological inhibition reduces stemness with paralleled differentiation and arrests cell cycle progression without causing appreciable apoptosis. Strikingly, the severity of antitumor effect of PRMT5 inhibition correlates with disease aggressiveness, with AR+ PCa being less affected. Molecular characterization pinpoints MYC, but not (or at least to a lesser degree) AR, as the main partner of PRMT5 to form a positive feedback loop to exacerbate malignancy in both AR+ and AR- PCa cells. Inspired by the surprising finding that PRMT5 negatively correlates with tumor immune infiltration and transcriptionally suppresses an immune-gene program, we further show that although PRMT5 inhibitor (PRMT5i) EPZ015666 or anti-PD-1 immunotherapy alone exhibits limited antitumor effects, combination of PRMT5i with anti-PD-1 displays superior efficacy in inhibiting castration-resistant PCa (CRPC) in vivo. Finally, to expand the potential use of PRMT5i through a synthetic lethality concept, we also perform a global CRISPR/Cas9 knockout screen to unravel that many clinical-grade drugs of known oncogenic pathways can be repurposed to target CRPC when used in combination with PRMT5i at low doses. Collectively, our findings establish a rationale to exploit PRMT5i in combination with immunotherapy or other targeted therapies to treat aggressive PCa.
Assuntos
Neoplasias da Próstata , Proteína-Arginina N-Metiltransferases , Proteína-Arginina N-Metiltransferases/genética , Proteína-Arginina N-Metiltransferases/metabolismo , Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Masculino , Humanos , Animais , Neoplasias da Próstata/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/tratamento farmacológico , Linhagem Celular Tumoral , Camundongos , Proliferação de Células/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Imunoterapia/métodos , Regulação Neoplásica da Expressão GênicaRESUMO
Immune checkpoint blockade (ICB) has emerged as a promising therapeutic option for hepatocellular carcinoma (HCC), but resistance to ICB occurs and patient responses vary. Here, we uncover protein arginine methyltransferase 3 (PRMT3) as a driver for immunotherapy resistance in HCC. We show that PRMT3 expression is induced by ICB-activated T cells via an interferon-gamma (IFNγ)-STAT1 signaling pathway, and higher PRMT3 expression levels correlate with reduced numbers of tumor-infiltrating CD8+ T cells and poorer response to ICB. Genetic depletion or pharmacological inhibition of PRMT3 elicits an influx of T cells into tumors and reduces tumor size in HCC mouse models. Mechanistically, PRMT3 methylates HSP60 at R446 to induce HSP60 oligomerization and maintain mitochondrial homeostasis. Targeting PRMT3-dependent HSP60 methylation disrupts mitochondrial integrity and increases mitochondrial DNA (mtDNA) leakage, which results in cGAS/STING-mediated anti-tumor immunity. Lastly, blocking PRMT3 functions synergize with PD-1 blockade in HCC mouse models. Our study thus identifies PRMT3 as a potential biomarker and therapeutic target to overcome immunotherapy resistance in HCC.
Assuntos
Carcinoma Hepatocelular , Chaperonina 60 , Neoplasias Hepáticas , Proteínas de Membrana , Nucleotidiltransferases , Proteína-Arginina N-Metiltransferases , Transdução de Sinais , Animais , Proteína-Arginina N-Metiltransferases/metabolismo , Proteína-Arginina N-Metiltransferases/genética , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Nucleotidiltransferases/metabolismo , Nucleotidiltransferases/genética , Humanos , Camundongos , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Chaperonina 60/metabolismo , Chaperonina 60/genética , Linhagem Celular Tumoral , Metilação , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Mitocôndrias/metabolismo , Camundongos Endogâmicos C57BL , DNA Mitocondrial/genética , DNA Mitocondrial/imunologia , DNA Mitocondrial/metabolismo , Interferon gama/metabolismo , Interferon gama/imunologia , MasculinoRESUMO
Gastrointestinal (GI) cancers, encompassing a range of malignancies within the digestive tract, present significant challenges in both diagnosis and treatment, reflecting a dire need for innovative therapeutic strategies. This article delves into the profound influence of non-histone methylation on the pathogenesis and evolution of gastrointestinal (GI) cancers. Non-histone proteins, undergoing methylation by enzymes such as Protein Arginine Methyltransferases (PRMTs) and Lysine Methyltransferases (KMTs), play pivotal roles in cellular signaling, metabolism, chromatin remodeling, and other processes crucial for cancer development. This review illuminates the complex mechanisms by which non-histone methylation affects key aspects of tumor biology, including oncogenesis, growth, proliferation, invasion, migration, metabolic reprogramming, and immune escape in GI malignancies. Highlighting recent discoveries, this work underscores the importance of non-histone methylation in cancer biology and its potential as a target for innovative therapeutic strategies aimed at improving outcomes for patients with GI cancers.
Assuntos
Neoplasias Gastrointestinais , Humanos , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/metabolismo , Neoplasias Gastrointestinais/patologia , Metilação , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Proteína-Arginina N-Metiltransferases/metabolismo , Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , AnimaisRESUMO
Strategies beyond hormone-related therapy need to be developed to improve prostate cancer mortality. Here, we show that FUBP1 and its methylation were essential for prostate cancer progression, and a competitive peptide interfering with FUBP1 methylation suppressed the development of prostate cancer. FUBP1 accelerated prostate cancer development in various preclinical models. PRMT5-mediated FUBP1 methylation, regulated by BRD4, was crucial for its oncogenic effect and correlated with earlier biochemical recurrence in our patient cohort. Suppressed prostate cancer progression was observed in various genetic mouse models expressing the FUBP1 mutant deficient in PRMT5-mediated methylation. A competitive peptide, which was delivered through nanocomplexes, disrupted the interaction of FUBP1 with PRMT5, blocked FUBP1 methylation, and inhibited prostate cancer development in various preclinical models. Overall, our findings suggest that targeting FUBP1 methylation provides a potential therapeutic strategy for prostate cancer management.
Assuntos
DNA Helicases , Proteínas de Ligação a DNA , Neoplasias da Próstata , Proteína-Arginina N-Metiltransferases , Proteínas de Ligação a RNA , Masculino , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Neoplasias da Próstata/metabolismo , Humanos , Animais , Camundongos , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Proteína-Arginina N-Metiltransferases/genética , Proteína-Arginina N-Metiltransferases/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Metilação , DNA Helicases/genética , DNA Helicases/metabolismo , Progressão da Doença , Linhagem Celular Tumoral , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Retinoblastoma (RB) is the most common intraocular malignancy among children and presents a certain mortality risk, especially in low- and middle-income countries. Clarifying the molecular mechanisms underlying the onset and progression of retinoblastoma is vital for devising effective cancer treatment approaches. PRMT1, a major type I PRMT, plays significant roles in cancer development. However, its expression and role in retinoblastoma are still unclear. Our research revealed a marked increase in PRMT1 levels in both retinoblastoma tissues and Y79 cells. The overexpression of PRMT1 in Y79 cells promoted their growth and cell cycle progression. Conversely, the suppression of PRMT1 hindered the growth of Y79 cells and impeded cell cycle progression. Mechanistically, PRMT1 mediated the growth of Y79 retinoblastoma cells by targeting the p53/p21/CDC2/Cyclin B pathway. Additionally, the ability of PRMT1 knockdown to suppress cell proliferation was also observed in vivo. Overall, PRMT1 could function as a potential target for therapeutic treatment in individuals with retinoblastoma.
Assuntos
Proliferação de Células , Inibidor de Quinase Dependente de Ciclina p21 , Proteína-Arginina N-Metiltransferases , Proteínas Repressoras , Neoplasias da Retina , Retinoblastoma , Proteína Supressora de Tumor p53 , Proteína-Arginina N-Metiltransferases/metabolismo , Proteína-Arginina N-Metiltransferases/genética , Retinoblastoma/patologia , Retinoblastoma/metabolismo , Retinoblastoma/genética , Humanos , Proliferação de Células/fisiologia , Neoplasias da Retina/patologia , Neoplasias da Retina/metabolismo , Neoplasias da Retina/genética , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/genética , Proteínas Repressoras/metabolismo , Proteínas Repressoras/genética , Proteína Quinase CDC2/metabolismo , Proteína Quinase CDC2/genética , Regulação Neoplásica da Expressão Gênica , Animais , Camundongos , Western Blotting , Ciclo Celular/fisiologia , Transdução de Sinais/fisiologia , Células Tumorais Cultivadas , Linhagem Celular Tumoral , Camundongos NusRESUMO
Phytophthora capsici, a pathogenic oomycete, poses a serious threat to global vegetable production. This study investigated the role of protein arginine methylation, a notable post-translational modification, in the epigenetic regulation of P. capsici. We identified and characterized five protein arginine methyltransferases (PRMTs) in P. capsici, with a focus on four putative type I PRMTs exhibiting similar functional domain. Deletion of PcPRMT3, a homolog of PRMT3, significantly affected mycelial growth, asexual spore development, pathogenicity, and stress responses in P. capsici. Transcriptome analyses indicated that absence of PcPRMT3 disrupted multiple biological pathways. The PcPRMT3 deletion mutant displayed heightened susceptibility to oxidative stress, correlated with the downregulation of genes involved in peroxidase and peroxisome activities. Additionally, PcPRMT3 acted as a negative regulator, modulating the transcription levels of specific elicitins, which in turn affects the defense response of host plant against P. capsici. Furthermore, PcPRMT3 was found to affect global arginine methylation levels in P. capsici, implying potential alterations in the functions of its substrate proteins.
Assuntos
Phytophthora , Doenças das Plantas , Proteína-Arginina N-Metiltransferases , Phytophthora/patogenicidade , Phytophthora/genética , Proteína-Arginina N-Metiltransferases/metabolismo , Proteína-Arginina N-Metiltransferases/genética , Doenças das Plantas/microbiologia , Arginina/metabolismo , Estresse Oxidativo/genética , MetilaçãoRESUMO
Breast cancer is the most common cancer diagnosed in women worldwide. Early-stage breast cancer is curable in ~70-80% of patients, while advanced metastatic breast cancer is considered incurable with current therapies. Breast cancer is a highly heterogeneous disease categorized into three main subtypes based on key markers orientating specific treatment strategies for each subtype. The complexity of breast carcinogenesis is often associated with epigenetic modification regulating different signaling pathways, involved in breast tumor initiation and progression, particularly by the methylation of arginine residues. Protein arginine methyltransferases (PRMT1-9) have emerged, through their ability to methylate histones and non-histone substrates, as essential regulators of cancers. Here, we present an updated overview of the mechanisms by which PRMT1 and PRMT5, two major members of the PRMT family, control important signaling pathways impacting breast tumorigenesis, highlighting them as putative therapeutic targets.
Assuntos
Neoplasias da Mama , Proteína-Arginina N-Metiltransferases , Proteínas Repressoras , Proteína-Arginina N-Metiltransferases/metabolismo , Proteína-Arginina N-Metiltransferases/genética , Humanos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Proteínas Repressoras/metabolismo , Proteínas Repressoras/genética , Transdução de Sinais , Metilação , Epigênese Genética , Animais , Regulação Neoplásica da Expressão GênicaRESUMO
Precancerous cervical lesions are metaplastic alterations of epithelial cells of the cervix, eventually developing into cervical cancer. Despite primary and secondary prevention, the burden of cervical cancer remains high globally. Protein arginine methyltransferases (PRMT) represent post-translational modifications that interact with multiple signalling pathways, playing a role in epithelial-mesenchymal transition. In complex with desmoglein-2 (DSG2), a cell adhesion protein, both participate in the progression of dysplastic changes with potential malignant development. The presented study was performed on archival paraffin-embedded blocks from adult women. The studied samples were categorised into low-grade and high-grade intraepithelial lesions. Immunohistochemical analysis was used to observe subcellular localisation, immunoreaction intensity, and percentage of PRMT5- and DSG2-expressing cells, followed by statistical analysis. Preliminary results identified statistically significant differences between the expression and subcellular localisation of proteins in question in low-grade and high-grade squamous intraepithelial lesions. The primary goal of the presented study is to perceive the involvement of PRMT5 and DSG2 in the initiation and progression of cervical lesions. Our observations indicate the potential of the assessed proteins as prognostic markers. However, further studies of PRMT5 and DSG2 are required to provide greater insight into cervical carcinogenesis.
Assuntos
Biomarcadores Tumorais , Desmogleína 2 , Lesões Pré-Cancerosas , Proteína-Arginina N-Metiltransferases , Neoplasias do Colo do Útero , Humanos , Feminino , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/metabolismo , Proteína-Arginina N-Metiltransferases/metabolismo , Proteína-Arginina N-Metiltransferases/análise , Desmogleína 2/metabolismo , Desmogleína 2/análise , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Lesões Pré-Cancerosas/patologia , Lesões Pré-Cancerosas/metabolismo , Adulto , Prognóstico , Pessoa de Meia-Idade , Imuno-Histoquímica , Displasia do Colo do Útero/patologia , Displasia do Colo do Útero/metabolismoRESUMO
Ferroptosis is a form of nonapoptotic cell death characterized by iron-dependent peroxidation of polyunsaturated phospholipids. However, much remains unknown about the regulators of ferroptosis. Here, using CRISPR-Cas9-mediated genetic screening, we identify protein arginine methyltransferase 1 (PRMT1) as a crucial promoter of ferroptosis. We find that PRMT1 decreases the expression of solute carrier family 7 member 11 (SLC7A11) to limit the abundance of intracellular glutathione (GSH). Moreover, we show that PRMT1 interacts with ferroptosis suppressor protein 1 (FSP1), a GSH-independent ferroptosis suppressor, to inhibit the membrane localization and enzymatic activity of FSP1 through arginine dimethylation at R316, thus reducing CoQ10H2 content and inducing ferroptosis sensitivity. Importantly, genetic depletion or pharmacological inhibition of PRMT1 in mice prevents ferroptotic events in the liver and improves the overall survival under concanavalin A (ConA) exposure. Hence, our findings suggest that PRMT1 is a key regulator of ferroptosis and a potential target for antiferroptosis therapeutics.
Assuntos
Ferroptose , Proteína-Arginina N-Metiltransferases , Proteína-Arginina N-Metiltransferases/metabolismo , Proteína-Arginina N-Metiltransferases/genética , Animais , Ferroptose/genética , Humanos , Camundongos , Sistemas CRISPR-Cas/genética , Camundongos Endogâmicos C57BL , Glutationa/metabolismo , Sistema y+ de Transporte de Aminoácidos/metabolismo , Sistema y+ de Transporte de Aminoácidos/genética , Masculino , Fígado/metabolismo , Proteínas Repressoras/metabolismo , Proteínas Repressoras/genética , Células HEK293RESUMO
Viral suppressor RNA silencing (VSR) is essential for successful infection. Nucleotide-binding and leucine-rich repeat (NLR)-based and autophagy-mediated immune responses have been reported to target VSR as counter-defense strategies. Here, we report a protein arginine methyltransferase 6 (PRMT6)-mediated defense mechanism targeting VSR. The knockout and overexpression of PRMT6 in tomato plants lead to enhanced and reduced disease symptoms, respectively, during tomato bush stunt virus (TBSV) infection. PRMT6 interacts with and inhibits the VSR function of TBSV P19 by methylating its key arginine residues R43 and R115, thereby reducing its dimerization and small RNA-binding activities. Analysis of the natural tomato population reveals that two major alleles associated with high and low levels of PRMT6 expression are significantly associated with high and low levels of viral resistance, respectively. Our study establishes PRMT6-mediated arginine methylation of VSR as a mechanism of plant immunity against viruses.
Assuntos
Doenças das Plantas , Imunidade Vegetal , Proteína-Arginina N-Metiltransferases , Solanum lycopersicum , Proteína-Arginina N-Metiltransferases/metabolismo , Proteína-Arginina N-Metiltransferases/genética , Doenças das Plantas/virologia , Doenças das Plantas/imunologia , Solanum lycopersicum/virologia , Solanum lycopersicum/imunologia , Solanum lycopersicum/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Proteínas de Plantas/imunologia , Arginina/metabolismo , Metilação , Interferência de RNA , Proteínas Virais/metabolismo , Proteínas Virais/genética , Interações Hospedeiro-Patógeno/imunologia , Regulação da Expressão Gênica de PlantasRESUMO
Breast cancer is a major public health concern worldwide, being the most commonly diagnosed cancer among women and a leading cause of cancer-related deaths. Recent studies have highlighted the significance of non-histone methylation in breast cancer, which modulates the activity, interaction, localization, and stability of target proteins. This regulation affects critical processes such as oncogenesis, tumor growth, proliferation, invasion, migration, and immune responses. This review delves into the enzymes responsible for non-histone methylation, such as protein arginine methyltransferases (PRMTs), lysine methyltransferases (KMTs), and demethylases, and explores their roles in breast cancer. By elucidating the molecular mechanisms and functional consequences of non-histone methylation, this review aims to provide insights into novel therapeutic strategies targeting these pathways. The therapeutic potential of targeting non-histone methylation to overcome drug resistance and enhance treatment efficacy in breast cancer is also discussed, highlighting promising avenues for future research and clinical applications.