Molecular characterization, immune functions and DNA protective effects of peroxiredoxin-1 gene in Antheraea pernyi.

Peroxiredoxins are antioxidant proteins that detoxify peroxynitrite, hydrogen peroxide, and organic hydroperoxides, impacting various physiological processes such as immune responses, apoptosis, cellular homeostasis, and so on. In the present study, we identified and characterized peroxiredoxin 1 from Antheraea pernyi (thereafter designated as ApPrx-1) that encodes a predicted 195 amino acid residue protein with a 21.8 kDa molecular weight. Quantitative real-time PCR analysis revealed that the mRNA level of ApPrx-1 was highest in the hemocyte, fat body, and midgut. Immune-challenged larval fat bodies and hemocytes showed increased ApPrx-1 transcript. Moreover, ApPrx-1 expression was induced in hemocytes and the whole body of A. pernyi following exogenous H2O2 administration. A DNA cleavage assay performed using recombinant ApPrx-1 protein showed that rApPrx-1 protein manifests the ability to protect supercoiled DNA damage from oxidative stress. To test the rApPrx-1 protein antioxidant activity, the ability of the rApPrx-1 protein to remove H2O2 was assessed in vitro using rApPrx-1 protein and DTT, while BSA + DDT served as a control group. The results revealed that ApPrx-1 can efficiently remove H2O2 in vitro. In the loss of function analysis, we found that ApPrx-1 significantly increased the levels of H2O2 in ApPrx-1-depleted larvae compared to the control group. We also found a significantly lower survival rate in the larvae in which ApPrx-1 was knocked down. Interestingly, the antibacterial activity was significantly higher in the ApPrx-1 depleted larvae, compared to the control. Collectively, evidence strongly suggests that ApPrx-1 may regulate physiological activities and provides a reference for further studies to validate the utility of the key genes involved in reliving oxidative stress conditions and regulating the immune responses of insects.

Mechanism of Notch Signaling Pathway in Malignant Progression of Glioblastoma and Targeted Therapy.

Glioblastoma multiforme (GBM) is the most aggressive form of glioma and the most common primary tumor of the central nervous system. Despite significant advances in clinical management strategies and diagnostic techniques for GBM in recent years, it remains a fatal disease. The current standard of care includes surgery, radiation, and chemotherapy, but the five-year survival rate for patients is less than 5%. The search for a more precise diagnosis and earlier intervention remains a critical and urgent challenge in clinical practice. The Notch signaling pathway is a critical signaling system that has been extensively studied in the malignant progression of glioblastoma. This highly conserved signaling cascade is central to a variety of biological processes, including growth, proliferation, self-renewal, migration, apoptosis, and metabolism. In GBM, accumulating data suggest that the Notch signaling pathway is hyperactive and contributes to GBM initiation, progression, and treatment resistance. This review summarizes the biological functions and molecular mechanisms of the Notch signaling pathway in GBM, as well as some clinical advances targeting the Notch signaling pathway in cancer and glioblastoma, highlighting its potential as a focus for novel therapeutic strategies.

Moracin D suppresses cell growth and induces apoptosis via targeting the XIAP/PARP1 axis in pancreatic cancer.

BACKGROUND: Pancreatic cancer, a tumor with a high metastasis rate and poor prognosis, is among the deadliest human malignancies. Investigating effective drugs for their treatment is imperative. Moracin D, a natural benzofuran compound isolated from Morus alba L., shows anti-inflammation and anti-breast cancer properties and is effective against Alzheimer's disease. However, the effect and mechanism of Moracin D action in pancreatic cancer remain obscure. PURPOSE: To investigate the function and molecular mechanism of Moracin D action in repressing the malignant progression of pancreatic cancer. METHODS: Pancreatic cancer cells were treated with Moracin D, and cell proliferation was evaluated by cell counting kit-8 (CCK-8) and immunofluorescence assays. The clonogenicity of pancreatic cancer cells was assessed based on plate colony formation and soft agar assay. Flow cytometry was used to detect cell apoptosis. The expression of proteins related to the apoptosis pathway was determined by Western blot analysis. Moracin D and XIAP were subjected to docking by auto-dock molecular docking analysis. Ubiquitination levels of XIAP and the interaction of XIAP and PARP1 were assessed by co-immunoprecipitation analysis. Moracin D's effects on tumorigenicity were assessed by a tumor xenograft assay. RESULTS: Moracin D inhibited cell proliferation, induced cell apoptosis, and regulated the protein expression of molecules involved in caspase-dependent apoptosis pathways. Moracin D suppressed clonogenicity and tumorigenesis of pancreatic cancer cells. Mechanistically, XIAP could interact with PARP1 and stabilize PARP1 by controlling its ubiquitination levels. Moracin D diminished the stability of XIAP and decreased the expression of XIAP by promoting proteasome-dependent XIAP degradation, further blocking the XIAP/PARP1 axis and repressing the progression of pancreatic cancer. Moracin D could dramatically improve the chemosensitivity of gemcitabine in pancreatic cancer cells. CONCLUSION: Moracin D repressed cell growth and tumorigenesis, induced cell apoptosis, and enhanced the chemosensitivity of gemcitabine through the XIAP/PARP1 axis in pancreatic cancer. Moracin D is a potential therapeutic agent or adjuvant for pancreatic cancer.

OTUD4 promotes the progression of glioblastoma by deubiquitinating CDK1 and activating MAPK signaling pathway.

Glioblastoma, IDH-Wild type (GBM, CNS WHO Grade 4) is a highly heterogeneous and aggressive primary malignant brain tumor with high morbidity, high mortality, and poor patient prognosis. The global burden of GBM is increasing notably due to limited treatment options, drug delivery problems, and the lack of characteristic molecular targets. OTU deubiquitinase 4 (OTUD4) is a potential predictive factor for several cancers such as breast cancer, liver cancer, and lung cancer. However, its function in GBM remains unknown. In this study, we found that high expression of OTUD4 is positively associated with poor prognosis in GBM patients. Moreover, we provided in vitro and in vivo evidence that OTUD4 promotes the proliferation and invasion of GBM cells. Mechanism studies showed that, on the one hand, OTUD4 directly interacts with cyclin-dependent kinase 1 (CDK1) and stabilizes CDK1 by removing its K11, K29, and K33-linked polyubiquitination. On the other hand, OTUD4 binds to fibroblast growth factor receptor 1 (FGFR1) and reduces FGFR1's K6 and K27-linked polyubiquitination, thereby indirectly stabilizing CDK1, ultimately influencing the activation of the downstream MAPK signaling pathway. Collectively, our results revealed that OTUD4 promotes GBM progression via OTUD4-CDK1-MAPK axis, and may be a prospective therapeutic target for GBM treatment.

[Sanggenon C inhibits glioblastoma cell migration and invasion by promoting ubiquitination of ß-catenin].

Glioblastoma is a malignant and highly invasive tumor, which requires new approaches to search for chemotherapeutic agents. Sanggenon C (SC) mainly exists in the root bark of white mulberry. Although its anti-tumor effects have been reported in some cancers, the mechanism remains unclear. In this study, we used microscopic observation, transwell assay, and immunofluorescence assay to verify the effect of Sanggenon C on the migration and invasion of glioblastoma cells. We then carried out the gene set enrichment analysis (GESA), real-time qPCR assay and ubiquitination assay to delineate the molecule mechanism by which Sanggenon C affects the migration and invasion ability of glioblastoma. With the addition of Sanggenon C, glioblastoma cells were rounded up, with the migration and invasion ability weakened as verified by transwell assay and immunofluorescence assay. The results of GESA suggested that SC might regulate the expression of genes associated with migration and invasion and affect the activity of Wnt/ß-catenin signaling pathway. Western blotting revealed that Sanggenon C promoted the ubiquitination of ß-catenin to reduce the levels of ß-catenin and its downstream proteins. This was further supported by the results of real-time qPCR analysis of target genes of ß-catenin. Taken together, SC inhibits glioblastoma cell migration and invasion by enhancing ß-catenin ubiquitination. Our work suggests a new direction for the treatment of glioblastoma.

Genomic and epigenetic characterization of the arsenic-induced oncogenic microRNA-21.

As one of the first identified oncogenic microRNAs, the precise details concerning the transcriptional regulation and function of microRNA-21 (miR-21) are still not completely established. The miR-21 gene is situated on chromosome 17q23.2, positioned at the 3'-UTR of the gene that encodes vacuole membrane protein-1 (VMP1). In this current study, we presented evidence indicating that miR-21 possesses its own gene promoter, which can be found in the intron 10 of the VMP1 gene. Chromatin immunoprecipitation followed by global DNA sequencing (ChIP-seq) revealed the presence of a broad H3K4me3 peak spanning the entire gene body of the primary miR-21 and the existence of super-enhancer clusters in the close proximity to both the miR-21 gene promoter and the transcription termination site in arsenic (As3+)-induced cancer stem-like cells (CSCs) and human induced pluripotent stem cells (hiPSCs). In non-transformed human bronchial epithelial cells (BEAS-2B), As3+ treatment enhanced Nrf2 binding to both the host gene VMP1 of miR-21 and the miR-21 gene. Knockout of Nrf2 inhibited both the basal and As3+-induced expressions of miR-21. Furthermore, the As3+-enhanced Nrf2 peaks in ChIP-seq fully overlap with these super-enhancers enriched with H3K4me1 and H3K27ac in the miR-21 gene, suggesting that Nrf2 may coordinate with other transcription factors through the super-enhancers to regulate the expression of miR-21 in cellular response to As3+. These findings demonstrate the unique genetic and epigenetic characteristics of miR-21 and may provide insights into understanding the novel mechanisms linking environmental As3+ exposure and human cancers.

Gastrointestinal Cancer Therapeutics via Triggering Unfolded Protein Response and Endoplasmic Reticulum Stress by 2-Arylbenzofuran.

Gastrointestinal cancers are a major global health challenge, with high mortality rates. This study investigated the anti-cancer activities of 30 monomers extracted from Morus alba L. (mulberry) against gastrointestinal cancers. Toxicological assessments revealed that most of the compounds, particularly immunotoxicity, exhibit some level of toxicity, but it is generally not life-threatening under normal conditions. Among these components, Sanggenol L, Sanggenon C, Kuwanon H, 3'-Geranyl-3-prenyl-5,7,2',4'-tetrahydroxyflavone, Morusinol, Mulberrin, Moracin P, Kuwanon E, and Kuwanon A demonstrate significant anti-cancer properties against various gastrointestinal cancers, including colon, pancreatic, and gastric cancers. The anti-cancer mechanism of these chemical components was explored in gastric cancer cells, revealing that they inhibit cell cycle and DNA replication-related gene expression, leading to the effective suppression of tumor cell growth. Additionally, they induced unfolded protein response (UPR) and endoplasmic reticulum (ER) stress, potentially resulting in DNA damage, autophagy, and cell death. Moracin P, an active monomer characterized as a 2-arylbenzofuran, was found to induce ER stress and promote apoptosis in gastric cancer cells, confirming its potential to inhibit tumor cell growth in vitro and in vivo. These findings highlight the therapeutic potential of Morus alba L. monomers in gastrointestinal cancers, especially focusing on Moracin P as a potent inducer of ER stress and apoptosis.

Screening of anti-melanoma compounds from Morus alba L.: Sanggenon C promotes melanoma cell apoptosis by disrupting intracellular Ca2+ homeostasis.

ETHNOPHARMACOLOGICAL RELEVANCE: Morus alba L. is a widespread plant that has long been considered to have remarkable medical values, including anti-inflammation in Traditional Chinese Medicine (TCM). The components of Morus Alba L. constituents have been extensively studied and have been shown to have high prospects for cancer therapy. However, limited investigations have been done on the bioactive compounds in Morus alba L. AIM OF THE STUDY: This study aimed to systematically examine the anticancer properties of 28 commercially available compounds from Morus alba L. against melanoma cells in vitro. Additionally, the anticancer mechanisms of the bioactive compound exhibiting the most significant potential were further studied. MATERIALS AND METHODS: The anti-proliferative effects of Morus alba L.-derived compounds on melanoma cells were determined by colony formation assays. Their effects on cell viability and apoptosis were determined using the CCK8 assay and flow cytometry, respectively. The binding affinity of identified Morus alba L. compounds with anticancer activities towards melanoma targets was analyzed via molecular docking. The molecular mechanism of Sanggenon C was explored using soft agar assays, EdU incorporation assays, flow cytometry, western blotting, transcriptome analysis, and xenograft assays. RESULTS: Based on colony formation assays, 11 compounds at 20 µM significantly inhibited colony growth on a panel of melanoma cells. These compounds displayed IC50 values (half maximal inhibitory concentrations) ranging from 5 µM to 30 µM. Importantly, six compounds were identified as novel anti-melanoma agents, including Sanggenon C, 3'-Geranyl-3-prenyl-2',4',5,7-tetrahydroxyflavone, Moracin P, Moracin O, Kuwanon A, and Kuwanon E. Among them, Sanggenon C showed the most potent effects, with an IC50 of about 5 µM, significantly reducing proliferation and inducing apoptosis in melanoma cells. Based on the xenograft model assay, Sanggenon C significantly inhibited melanoma cell proliferation in vivo. Sanggenon C triggered ER stress in a dose-dependent manner, which further disrupted cellular calcium ion (Ca2+) homeostasis. The Ca2+ chelator BAPTA partially restored cell apoptosis induced by Sanggenon C, confirming that Ca2+ signaling contributed to the anticancer activity of Sanggenon C against melanoma. CONCLUSIONS: In our study, 11 compounds demonstrated anti-melanoma properties. Notably, Sanggenon C was found to promote apoptosis by disrupting the intracellular calcium homeostasis in melanoma cells. This study provides valuable information for the future development of novel cancer therapeutic agents from Morus alba L.

GATA binding protein 6 regulates apoptosis in silkworms through interaction with poly (ADP-ribose) polymerase.

The GATA family of genes plays various roles in crucial biological processes, such as development, cell differentiation, and disease progression. However, the roles of GATA in insects have not been thoroughly explored. In this study, a genome-wide characterization of the GATA gene family in the silkworm, Bombyx mori, was conducted, revealing lineage-specific expression profiles. Notably, GATA6 is ubiquitously expressed across various developmental stages and tissues, with predominant expression in the midgut, ovaries, and Malpighian tubules. Overexpression of GATA6 inhibits cell growth and promotes apoptosis, whereas, in contrast, knockdown of PARP mitigates the apoptotic effects driven by GATA6 overexpression. Co-immunoprecipitation (co-IP) has demonstrated that GATA6 can interact with Poly (ADP-ribose) polymerase (PARP), suggesting that GATA6 may induce cell apoptosis by activating the enzyme's activity. These findings reveal a dynamic and regulatory relationship between GATA6 and PARP, suggesting a potential role for GATA6 as a key regulator in apoptosis through its interaction with PARP. This research deepens the understanding of the diverse roles of the GATA family in insects, shedding light on new avenues for studies in sericulture and pest management.

Peroxiredoxin-2 gene in Antheraea pernyi modulates immune functions and protect DNA damage.

Peroxiredoxins have been shown to protect insects from oxidative damage and to play a role in the immune system. In the present study, we cloned and characterized the Antheraea pernyi peroxiredoxin 2 (ApPrx-2) gene, then assessed its functional roles. The ApPrx-2 gene has a 687 bp open reading frame that encodes a protein with 288 amino acid residues. Quantitative real-time PCR analysis revealed that the mRNA levels of ApPrx-2 were highest in the hemocytes. Immune challenge assay revealed that ApPrx-2 transcription could be induced after microbial challenge. A DNA cleavage assay employing recombinant ApPrx-2 protein and a metal-catalyzed oxidation system showed that rApPrx-2 protein could protect supercoiled DNA against oxidative stress. The protein antioxidant activity of rApPrx-2 was examined, and it was found that rApPrx-2 exhibited a high level of antioxidant activity by removing H2O2. In addition, ApPrx-2 knockdown larvae had higher H2O2 levels and a lower survival rate when compared to controls. Interestingly, the antibacterial activity was significantly higher in ApPrx-2 depleted larvae compared with control. Overall, our findings indicate that ApPrx-2 may be involved in a range of physiological functions of A. pernyi, as it protects supercoiled DNA from oxidative stress and regulates antibacterial activity.

Histone demethylase KDM4B accelerates the progression of glioblastoma via the epigenetic regulation of MYC stability.

BACKGROUND: Glioblastoma (GBM) is the most malignant and invasive human brain tumor. Histone demethylase 4B (KDM4B) is abnormally expressed in GBM, but the molecular mechanisms by which KDM4B affects the malignant tumor progression are not well defined. METHODS: GBM cell lines and xenograft tumor samples were subjected to quantitative PCR (qPCR), Western blot, immunohistochemical staining (IHC), as well as ubiquitination, immunoprecipitation (IP), and chromatin immunoprecipitation (ChIP) assays to investigate the role of KDM4B in the progression of GBM. RESULTS: Here, we report that KDM4B is an epigenetic activator of GBM progression. Abnormal expression of KDM4B is correlated with a poor prognosis in GBM patients. In GBM cell lines, KDM4B silencing significantly inhibited cell survival, proliferation, migration, and invasion, indicating that KDM4B is essential for the anchorage-independent growth and tumorigenic activity of GBM cells. Mechanistically, KDM4B silencing led to downregulation of the oncoprotein MYC and suppressed the expression of cell cycle proteins and epithelial-to-mesenchymal transition (EMT)-related proteins. Furthermore, we found that KDM4B regulates MYC stability through the E3 ligase complex SCFFBXL3+CRY2 and epigenetically activates the transcription of CCNB1 by removing the repressive chromatin mark histone H3 lysine 9 trimethylation (H3K9me3). Finally, we provide evidence that KDM4B epigenetically activates the transcription of miR-181d-5p, which enhances MYC stability. CONCLUSIONS: Our study has uncovered a KDM4B-dependent epigenetic mechanism in the control of tumor progression, providing a rationale for utilizing KDM4B as a promising therapeutic target for the treatment of MYC-amplified GBM.

Predictive value of CCL2 in the prognosis and immunotherapy response of glioblastoma multiforme.

BACKGROUND: Glioblastoma multiforme (GBM) is the most common and lethal primary brain tumor with a poor prognosis. The C-C motif chemokine ligand 2 (CCL2) has shown abnormal expression associated with progression of multiple malignancies, however, its role in predicting the prognosis and immunotherapy response of GBM remains poorly understood. RESULTS: CCL2 was highly expressed in GBM as analyzed by integrating CGGA, GEPIA and UALCAN online platforms, and further verified by histologic examinations, qRT-PCR analysis, and independent GEO datasets. CCL2 could serve as an independent prognostic factor for both the poor overall survival and progression-free survival of GBM patients based on TCGA data, univariate and multivariate cox analyses. Functional enrichment analysis revealed that CCL2 mainly participated in the regulation of chemokine signaling pathway and inflammatory response. Further, CCL2 expression was positively correlated with CD4 T cells, macrophages, neutrophils and myeloid dendritic cells infiltrating GBM as calculated by the TIMER2.0 algorithm. Importantly, the tumor immune dysfunction and exclusion (TIDE) algorithm showed that in CCL2-high GBM group, the expression of CD274, CTLA4, HAVCR2 and other immune checkpoints were significantly increased, and the immune checkpoint blockade (ICB) therapy was accordingly more responsive. CONCLUSIONS: CCL2 can be used as a predictor of prognosis as well as immunotherapy response in GBM, offering potential clinical implications.

Morusinol Extracted from Morus alba Inhibits Cell Proliferation and Induces Autophagy via FOXO3a Nuclear Accumulation-Mediated Cholesterol Biosynthesis Obstruction in Colorectal Cancer.

The incidence rate of colorectal cancer (CRC) has been increasing significantly in recent years, and it is urgent to develop novel drugs that have more effects for its treatment. It has been reported that many molecules extracted from the root bark of Morus alba L. (also known as Cortex Mori) have antitumor activities. In our study, we identified morusinol as a promising anticancer agent by selecting from 30 molecules extracted from Morus alba L. We found that morusinol treatment suppressed cell proliferation and promoted apoptosis of CRC cells in vitro. Besides this, we observed that morusinol induced cytoprotective autophagy. The GO analysis of differentially expressed genes from RNA-seq data showed that morusinol affected cholesterol metabolism. Then we found that key enzyme genes in the cholesterol biosynthesis pathway as well as the sterol regulatory element binding transcription factor 2 (SREBF2) were significantly downregulated. Furthermore, additional cholesterol treatment reversed the anti-CRC effect of morusinol. Interestingly, we also found that morusinol treatment could promote forkhead box O3 (FOXO3a) nuclear accumulation, which subsequently suppressed SREBF2 transcription. Then SREBF2-controlled cholesterol biosynthesis was blocked, resulting in the suppression of cell proliferation, promotion of apoptosis, and production of autophagy. The experiments in animal models also showed that morusinol significantly impeded tumor growth in mice models. Our results suggested that morusinol may be used as a candidate anticancer drug for the treatment of CRC.

Kuwanon H Inhibits Melanoma Growth through Cytotoxic Endoplasmic Reticulum Stress and Impaired Autophagy Flux.

Although great progress has been made recently in targeted and immune-based therapies, additional treatments are needed for most melanoma patients due to acquired chemoresistance, recurrence, or metastasis. Elevated autophagy is required for the pathogenesis of melanoma to attenuate metabolic stress, protecting cancer cells from chemotherapeutics or radiation. Thus, intervention with autophagy is a promising strategy for melanoma treatment. Here, we examined a novel antimelanoma natural compound named kuwanon H (KuH), which significantly inhibited melanoma cell growth in vitro/vivo. Mechanistically, KuH induced cytotoxic endoplasmic reticulum (ER) stress, which inhibited cell viability and induced apoptosis. Meanwhile, KuH-induced ER stress mediated autophagysome formation through the ATF4-DDIT3-TRIB3-AKT-MTOR axis. Importantly, KuH impaired autophagy flux, which contributed to the anticancer effects of KuH. Finally, our results showed that KuH enhanced the sensitivity of melanoma cells to cisplatin, both in vitro and in vivo, by impairing autophagy degradation of reactive oxygen species and damaged mitochondria. Our findings indicate that KuH is a promising candidate anticancer natural product for melanoma therapy.

The applications of functional materials-based nano-formulations in the prevention, diagnosis and treatment of chronic inflammation-related diseases.

Chronic inflammation, in general, refers to systemic immune abnormalities most often caused by the environment or lifestyle, which is the basis for various skin diseases, autoimmune diseases, cardiovascular diseases, liver diseases, digestive diseases, cancer, and so on. Therapeutic strategies have focused on immunosuppression and anti-inflammation, but conventional approaches have been poor in enhancing the substantive therapeutic effect of drugs. Nanomaterials continue to attract attention for their high flexibility, durability and simplicity of preparation, as well as high profitability. Nanotechnology is used in various areas of clinical medicine, such as medical diagnosis, monitoring and treatment. However, some related problems cannot be ignored, including various cytotoxic and worsening inflammation caused by the nanomaterials themselves. This paper provides an overview of functional nanomaterial formulations for the prevention, diagnosis and treatment of chronic inflammation-related diseases, with the intention of providing some reference for the enhancement and optimization of existing therapeutic approaches.

AKIP1 accelerates glioblastoma progression through stabilizing EGFR expression.

A Kinase Interacting Protein 1 (AKIP1) is found to be overexpressed in a variety of human cancers and associated with patients' worse prognosis. Several studies have established AKIP1's malignant functions in tumor metastasis, angiogenesis, and chemoradiotherapy resistance. However, the mechanism of AKIP1 involved in accelerating glioblastoma (GBM) progression remains unknown. Here, we showed that the expression of AKIP1 was positively correlated with the glioma pathological grades. Down-regulating AKIP1 greatly impaired the proliferation, colony formation, and tumorigenicity of GBM cells. In terms of the mechanism, AKIP1 cooperates with transcriptional factor Yin Yang 1 (YY1)-mediated Heat Shock Protein 90 Alpha Family Class A Member 1 (HSP90AA1) transcriptional activation, enhancing the stability of Epidermal Growth Factor Receptor (EGFR). YY1 was identified as a potential transcriptional factor of HSP90AA1 and directly interacts with AKIP1. The overexpression of HSP90α significantly reversed AKIP1 depletion incurred EGFR instability and the blocked cell proliferation. Moreover, we further investigated the interacted pattern between EGFR and HSP90α. These findings established that AKIP1 acted as a critical oncogenic factor in GBM and uncovered a novel regulatory mechanism in EGFR aberrant expression.

Methylation across the central dogma in health and diseases: new therapeutic strategies.

The proper transfer of genetic information from DNA to RNA to protein is essential for cell-fate control, development, and health. Methylation of DNA, RNAs, histones, and non-histone proteins is a reversible post-synthesis modification that finetunes gene expression and function in diverse physiological processes. Aberrant methylation caused by genetic mutations or environmental stimuli promotes various diseases and accelerates aging, necessitating the development of therapies to correct the disease-driver methylation imbalance. In this Review, we summarize the operating system of methylation across the central dogma, which includes writers, erasers, readers, and reader-independent outputs. We then discuss how dysregulation of the system contributes to neurological disorders, cancer, and aging. Current small-molecule compounds that target the modifiers show modest success in certain cancers. The methylome-wide action and lack of specificity lead to undesirable biological effects and cytotoxicity, limiting their therapeutic application, especially for diseases with a monogenic cause or different directions of methylation changes. Emerging tools capable of site-specific methylation manipulation hold great promise to solve this dilemma. With the refinement of delivery vehicles, these new tools are well positioned to advance the basic research and clinical translation of the methylation field.

PRMT1 promotes the proliferation and metastasis of gastric cancer cells by recruiting MLXIP for the transcriptional activation of the ß-catenin pathway.

Protein arginine methyltransferase 1 (PRMT1), a type I PRMT, is overexpressed in gastric cancer (GC) cells. To elucidate the function of PRMT1 in GC, PRMT1 expression in HGC-27 and MKN-45 cells was knocked down by short hairpin RNA (shRNA) or inhibited by PRMT1 inhibitors (AMI-1 or DCLX069), which resulted in inhibition of GC cell proliferation, migration, invasion, and tumorigenesis in vitro and in vivo. MLX-interacting protein (MLXIP) and Kinectin 1 (KTN1) were identified as PRMT1-binding proteins. PRMT1 recruited MLXIP to the promoter of ß-catenin, which induced ß-catenin transcription and activated the ß-catenin signaling pathway, promoting GC cell migration and metastasis. Furthermore, KTN1 inhibited the K48-linked ubiquitination of PRMT1 by decreasing the interaction between TRIM48 and PRMT1. Collectively, our findings reveal a mechanism by which PRMT1 promotes cell proliferation and metastasis mediated by the ß-catenin signaling pathway.

Pseudotyped lentiviral vectors: Ready for translation into targeted cancer gene therapy?

Gene therapy holds great promise for curing cancer by editing the deleterious genes of tumor cells, but the lack of vector systems for efficient delivery of genetic material into specific tumor sites in vivo has limited its full therapeutic potential in cancer gene therapy. Over the past two decades, increasing studies have shown that lentiviral vectors (LVs) modified with different glycoproteins from a donating virus, a process referred to as pseudotyping, have altered tropism and display cell-type specificity in transduction, leading to selective tumor cell killing. This feature of LVs together with their ability to enable high efficient gene delivery in dividing and non-dividing mammalian cells in vivo make them to be attractive tools in future cancer gene therapy. This review is intended to summarize the status quo of some typical pseudotypings of LVs and their applications in basic anti-cancer studies across many malignancies. The opportunities of translating pseudotyped LVs into clinic use in cancer therapy have also been discussed.