ObjectiveTo investigate the clinical characteristics and identify prognostic factors in patients with newly diagnosed multiple myeloma (NDMM) who presenting with hypercalcemia.MethodsWe retrospectively analyzed clinical and laboratory data from 82 NDMM patients with hypercalcemia who were admitted to the Department of Hematology at Zhongda Hospital (Southeast University) and Jiangning Hospital (Nanjing Medical University) between January 2015 and December 2024. 80 patients without hypercalcemia were randomly selected as a control group for comparison. Prognostic evaluations were based on overall survival (OS), progression-free survival (PFS), and minimal residual disease (MRD) status. Survival rates were estimated using the Kaplan–Meier method, with univariate analyses performed via the Log-rank test and multivariate analyses utilizing the Cox proportional hazards regression model.ResultsThe cohort comprised 82 patients (51 males, 31 females). By the end of the follow-up period, with the median follow-up time was 51 months (range, 6–128): 59 patients had died and 23 were alive. Univariate analysis revealed that cytogenetic abnormalities (detected by FISH), serum creatinine, ferritin, MRD status, and serum calcium levels significantly affected both OS and PFS. Multivariate Cox regression demonstrated that the presence of ≤ 1 FISH abnormality and MRD negativity were independent protective factors for OS. Notably, elevated serum ferritin (≥500 ng/mL), a marker previously underexplored in this context, emerged as a robust independent risk factor for both OS and PFS. Severe hypercalcemia (≥3.5 mmol/L) was also identified as an independent risk factor for both OS and PFS. For PFS, MRD negativity remained an independent protective factor, whereas ferritin ≥500 ng/mL and serum calcium ≥3.5 mmol/L were identified as independent risk factors.ConclusionNDMM patients with hypercalcemia exhibited a substantial tumor burden, heterogeneous clinical manifestations, and a high rate of early mortality. Prompt correction of serum calcium levels, with adjustment for concurrent hypoalbuminemia, is imperative. Early detection and optimal management of hypercalcemia are essential to refining treatment strategies and improving survival outcomes.

Introduction Minimal Change Disease (MCD) represents a prevalent pathological cause of nephrotic syndrome. While podocyte injury is recognized as the direct cause of proteinuria in MCD, aberrant T-cell activation is a key driver of this podocyte damage. However, the absence of T-cell infiltration in renal biopsies and ineffectiveness of immunosuppressive therapy in a subset of patients suggest the existence of undiscovered key mechanisms underlying MCD immunopathogenesis. Objectives This study investigates the role of podocyte-derived exosomes (Pdo-Exos) in T cell activation via antigen presentation in MCD. Methods Using an in vitro co-culture system, a puromycin aminonucleoside (PAN)-induced MCD mouse model, and clinical samples, we evaluated the immunostimulatory capacity of Pdo-Exos, focusing on antigen presentation via MHC-I and Rab27a-regulated exosome secretion. Results Pdo-Exos activated CD8+ T cells through MHC-I without promoting proliferation, indicating a role for dendritic cell-mediated cross-presentation. In OT-I mice, OVA-loaded Pdo-Exos exacerbated proteinuria and activated both tissue-resident and lymphoid T cells. MCD patients exhibited increased circulating activated T cells, and their podocyte exosomes showed significantly elevated MHC-I and co-stimulatory molecule CD80. Rab27a-dependent exosome secretion exacerbated disease severity, while inhibition of Rab27a mitigated proteinuria and inflammation. Conclusion Podocyte-derived exosomes mediate CD8+ T cell activation by acting as antigen-presenting vesicles, with DCs facilitating T cell expansion. Rab27a-dependent exosome secretion contributes to MCD progression, highlighting a novel therapeutic strategy.

Protein neddylation is a post-translational modification process that modifies the functional state of proteins by conjugating NEDD8, a ubiquitin-like polypeptide, to the lysine residues of substrates. In various cancers, neddylation is upregulated and implicated in cancer progression via modulating cell cycle-related proteins. However, in colorectal cancer (CRC), the relationship between neddylation and the cell cycle remains incompletely understood. Here, by leveraging single-cell and bulk transcriptome data, we demonstrated that neddylation is associated with G2M phase progression in CRC. Through bioinformatic analysis, we identified ubiquitin conjugating enzyme E2 M (UBE2M) as a molecular bridge spanning neddylation and the cell cycle in CRC. To elucidate how UBE2M promotes CRC progression, we conducted in vivo and in vitro experiments to confirm the role of UBE2M in neddylating USP39, which in turn modulates the deubiquitination of PABPC1, enhances the translation efficiency of CCNB1 and propels the cell cycle progression of CRC. Regarding clinical application, we identified micafungin as an inhibitor of UBE2M capable of suppressing the regulatory axis and, consequently, hindering CRC progression. Therefore, this study underscores the potential role of UBE2M in bridging neddylation with the cell cycle and holds promise for advancing targeted therapies in CRC treatment.

Colorectal cancer remains a major cause of cancer mortality, with limited sensitivity in current diagnostics. Aberrant DNA methylation in expression-regulating sites shows biomarker potential, though few studies explore such methylation-based diagnostic tools for colorectal cancer. We conducted genome-wide DNA methylation and RNA sequencing on matched colorectal cancer and normal tissues to identify expression-related differentially methylated CpG sites (DMCs). Diagnostic models were constructed with training and validation sets of 689 samples. Machine learning techniques (random forest, elastic net, support vector machine) were employed to identify optimal diagnostic markers. Methylation-specific PCR confirmed marker-host gene regulatory relationships, and targeted bisulfite sequencing validated these markers in an independent cohort of 200 samples. Host genes roles in colorectal cancer pathogenesis were further investigated through in vivo and in vitro assays and tissue microarray analysis. We identified 64,824 DMCs in colorectal cancer, with 442 associated with gene expression. These sites impact transcription factor binding, and their host genes are linked to chemotherapy resistance. Diagnostic panels showed high efficacy, with methylation changes significantly impacting RNA and protein expression of host genes. Markers cg16851417, cg19498960, and cg16302790 were validated in blood for noninvasive screening. Clustering expression-related DMCs with similar methylation patterns may facilitate diagnostic tools development. Host genes SIM2, PDX1, and TNS4 influence colorectal cancer progression and may impact therapy response. Expression-related DMCs hold strong potential as colorectal cancer biomarkers, with implications for prognosis and therapy. The specific expression patterns of these DMCs in host genes support development of non-invasive blood-based diagnostic tools.

The RBR E3 ubiquitin ligase ARIH1 has been proven to induce specific ubiquitylation of substrates, thereby regulating cell proliferation and the cell cycle. However, the understanding of how ARIH1 influence cancer development is limited. This study revealed that ARIH1 is upregulated in colorectal cancer (CRC) cells and facilitates cell growth and metastasis. Clinically, high ARIH1 levels are linked to an unfavorable CRC prognosis. Mechanistically, ARIH1 directly interacts with PHB1 via its RING1+RBR+RING2 domains, catalyzing the K63-linked ubiquitination of PHB1 at lysine 186 (K186). The increased interaction between PHB1 and Akt through this modification results in PHB1 phosphorylation by Akt and its subsequent translocation into mitochondria, where it maintains mitochondrial stability and promotes oxidative phosphorylation (OXPHOS). Collectively, these findings demonstrate the role of ARIH1-mediated K63-linked ubiquitination of PHB1 in mitochondrial dynamics and OXPHOS, suggesting that it has potential as diagnostic biomarker and treatment target for CRC.

Small cell lung cancer (SCLC) is challenging to manage due to its high malignancy and early metastatic spread. Although initial chemoradiotherapy responses are common, resistance rapidly develops, and long-term efficacy remains limited. Immune checkpoint inhibitors (ICIs) overcome previous survival barriers, extending overall survival (OS) and progression-free survival (PFS) in extensive-stage SCLC. Nevertheless, absolute clinical benefits remain modest. To address efficacy limitations, current research focuses on optimizing first-line strategies by exploring multimodal regimens (e.g., adding targeted therapy or radiotherapy to chemoimmunotherapy) and advancing molecular subtyping for precision oncology. Furthermore, emerging therapies such as DLL3-targeted agents, bispecific antibodies (bsAbs), antibody-drug conjugates (ADCs), and chimeric antigen receptor T-cell (CAR-T) therapy continue to demonstrate clinical progress. This review synthesizes advances in SCLC management, focusing on mechanisms and clinical applications of multimodal strategies and novel therapies. It provides guidance for clinical decisions, research directions, and survival improvement.

Ceramide metabolism dysregulation links to colorectal cancer (CRC) progression, yet the mechanism remains unknown. d18:1/26:0 ceramide (C26) levels were elevated in patients with CRC and mouse models, which activated epidermal growth factor receptor (EGFR) by binding its extracellular region to promote cancer cell proliferation. The rise of C26 levels was mainly driven by heightened ceramide synthase 3 (CERS3) activity. High CERS3 expression generally accelerated tumor progression, yet some patients exhibited significant heterogeneity, suggesting endogenous metabolites available to affect CERS3 activity. We found that the abundance of Bacteroides cellulosilyticus affects tumor heterogeneity by producing riboflavin that inhibits CERS3 activity, thus delaying CRC progression. Moreover, aclidinium bromide, an FDA-approved drug, exhibited significant inhibitory effects on CERS3 activity, suggesting its potential application in CRC treatment. These findings elucidate the metabolic pathways and mechanisms underlying ceramide's impact on CRC, highlighting that targeting CERS3 inhibition represents a promising therapeutic strategy for CRC.

Cancer-associated fibroblasts (CAFs), known for facilitating the progression and metastasis of colorectal cancer (CRC), have become a promising therapeutic target. However, the significant heterogeneity of CAFs and their intricate crosstalk with tumor cells present substantial challenges in the development of precise and effective therapeutic strategies. Single-cell RNA sequencing (scRNA-seq) technology was used to identify various cell subtypes. Spatial transcriptomics (ST) was employed to map the spatial niches and colocalization patterns of these cell subtypes. Cell-cell interactions among these subtypes were analysed via CellChat and NicheNet software. Tumor cell invasion, migration, and proliferation were assessed through wound healing assays, transwell assays, colony formation assays, and xenograft mouse models. We identified a significant spatial colocalization between CTHRC1+ CAFs and a distinct subtype of malignant epithelial cells, both residing within the EMT-active spatial niche. Our results demonstrate that CTHRC1+ CAFs, as a major source of WNT5A, promote epithelial-mesenchymal transition (EMT) and enhance tumor cell invasiveness by upregulating MSLN expression in adjacent malignant epithelial cells. This signaling axis contributes significantly to CRC progression and metastasis. Targeting the CTHRC1+ CAF-WNT5A-MSLN signaling axis presents a promising therapeutic strategy for advanced CRC patients. Our study provides new insights into the role of CAFs in CRC progression and offers potential avenues for developing targeted therapies to disrupt this pathway.

This phase II study is designed to evaluate the combination therapy involving suvemcitug and envafolimab with FOLFIRI in microsatellite-stable or mismatch repair–proficient (MSS/pMMR) colorectal cancer (CRC) in the second-line treatment setting. This study is a non-randomized, open-label prospective study comprising multiple cohorts (NCT05148195). Here, we only report the data from the CRC cohort. Participants received envafolimab, suvemcitug, and FOLFIRI until disease progression, unacceptable toxicity, or voluntary withdrawal. The recommended dose (RD) and objective response rate (ORR) by investigator assessment were primary endpoints. Secondary endpoints comprised progression-free survival (PFS) and duration of response (DoR). Disease control rate (DCR), overall survival (OS), and safety were also analyzed. At the data cutoff, no dose-limiting toxicity event was observed in the safety run-in stage, and 2 mg/kg Q2W was declared as RD for suvemcitug combined with envafolimab and FORFIRI. Among 20 patients, 50.0

Recent single-cell RNA sequencing study suggested that CRABP1 expressing neurons in the arcuate nucleus (ARCCRABP1 neurons) were a distinct group of neurons. However, the physiological role of ARCCRABP1 neurons remains unexplored. Here, we demonstrated that ARCCRABP1 neurons played a crucial role in regulation of energy homeostasis in male mice. Ablation of ARCCRABP1 neurons resulted in obesity and a diabetic phenotype in mice. By employing chemogenetic or optogenetic manipulation techniques, the inhibition and activation of ARCCRABP1 neurons resulted in an increase and decrease in food intake, respectively. The axon terminals from these ARCCRABP1 neurons project to several brain regions implicated in feeding regulation such as PVH, BNST, PBN, and NTS. Optogenetic manipulation of these axons within these brain regions resulted in significant alterations of food intake behavior in mice. Furthermore, the electrophysiological studies demonstrated that the activation of ARCCRABP1 neurons induces depolarization in POMC neurons in the hypothalamus. The hormone stimulation studies showed that most of the ARCCRABP1 neurons respond to insulin. Collectively, our findings demonstrate that ARCCRABP1 neurons represent a distinct neuronal subtype involved in energy homeostasis regulation. POMC and AgRP neurons in hypothalamus were widely known to regulate energy balance. Here, authors show that ARCCRABP1 neurons are identified as a new player influencing appetite and metabolism.

For successful viral propagation within infected cells, the virus needs to overcome the cellular integrated stress response (ISR), triggered during viral infection, which, in turn, inhibits general protein translation. This paper reports a tactic employed by viruses to suppress the ISR by upregulating host cell polyribonucleotide nucleotidyltransferase 1 (PNPT1). The propagation of adenovirus, murine cytomegalovirus and hepatovirus within their respective host cells induces PNPT1 expression. Notably, when PNPT1 is knocked down, the propagation of all three viruses is prevented. Mechanistically, the inhibition of PNPT1 facilitates the relocation of mitochondrial double-stranded RNAs (mt-dsRNAs) to the cytoplasm, where they activate RNA-activated protein kinase (PKR). This activation leads to eukaryotic initiation factor 2α (eIF2α) phosphorylation, resulting in the suppression of translation. Furthermore, by scrutinizing the PNPT1 recognition element and screening 17,728 drugs and bioactive compounds approved by the US Food and Drug Administration, lanatoside C was identified as a potent PNPT1 inhibitor. This compound impedes the propagation of adenovirus, murine cytomegalovirus and hepatovirus, and suppresses production of the severe acute respiratory syndrome coronavirus-2 spike protein. These discoveries shed light on a novel strategy to impede pan-viral propagation by activating the host cell mt-dsRNA-PKR-eIF2α signalling axis.

Cell senescence genes play a vital role in the pathogenesis of colorectal cancer, a process that may involve the triggering of genetic variations and reversible phenotypes caused by epigenetic modifications. However, the specific regulatory mechanisms remain unclear. Using CellAge and The Cancer Genome Atlas databases and in-house RNA-seq data, DNA methylation-modified cellular senescence genes (DMCSGs) were validated by Support Vector Machine and correlation analyses. In 1150 cases and 1342 controls, we identified colorectal cancer risk variants in DMCSGs. The regulatory effects of gene, variant, and DNA methylation were explored through dual-luciferase and 5-azacytidine treatment experiments, complemented by multiple database analyses. Biological functions of key gene were evaluated via cell proliferation assays, SA-β-gal staining, senescence marker detection, and immune infiltration analyses. The genetic variant rs4558926 in the downstream of TACC3 was significantly associated with colorectal cancer risk (OR = 1.35, P = 3.22 × 10–4). TACC3 mRNA expression increased due to rs4558926 C > G and decreased DNA methylation levels. The CpG sites in the TACC3 promoter region were regulated by rs4558926. TACC3 knockdown decreased proliferation and senescence in colorectal cancer cells. In addition, subjects with high-TACC3 expression presented an immunosuppressive microenvironment. These findings provide insights into the involvement of genetic variants of cellular senescence genes in the development and progression of colorectal cancer.

Background and aims: The potential of urinary-derived extracellular vesicle (uEV) microRNAs (miRNAs) as noninvasive molecular biomarkers for identifying early-stage renal cell carcinoma (RCC) patients is rarely explored. The present study aims to explore the possibility of uEV miRNAs as novel molecular biomarkers for distinguishing early-stage RCC. Materials and methods: uEVs were extracted by ExoQuick-TCTM kit and miRNA concentrations were measured by RT-qPCR. ROC curves and bioinformatics analysis were employed to predict the diagnostic efficacy and regulatory mechanisms of dysregulated miRNAs. Results: Through a multiphase case-control study on uEV miRNAs screening, training, and validation in RCC cells (ACHN, Caki-1) and control cells (HK-2) and in uEVs of 125 RCC patients and 128 age- and sex-matched controls, we successfully identified four uEVs miRNAs (miR-135b-5p, miR-196b-5p, miR-200c-3p, and miR-203a-3p) were significantly and stably upregulated in RCC in vitro and in vivo. When adjusted with estimated glomerular filtration rate (eGFR), the AUC of the three-uEV miRNA panel (miR-135b-5p, miR-200c-3p, and miR-203a-3p) was 0.785 (95 % CI = 0.729-0.842, P < 0.0001) for discriminating RCC patients from controls. Notably, this panel exhibited similar performance in distinguishing early-stage (stage I) RCC patients, with an AUC of 0.786 (95 %CI = 0.727-0.844, P < 0.0001). Bioinformatics analysis predicted that candidate miRNAs were involved in cancer progressing. Conclusion: Our study identified a four uEV miRNAs panel (miR-135b-5p, miR-196b-5p, miR-200c-3p, and miR203a-3p) may serve as an auxiliary noninvasive indication of early-stage RCC.

Podocyte injury is a critical event in the pathogenesis of diabetic nephropathy (DN). Hyperglycemia, oxidative stress, inflammation, and other factors contribute to podocyte damage in DN. In this study, we demonstrate that signaling regulatory protein alpha (SIRPα) plays a pivotal role in regulating the metabolic and immune homeostasis of podocytes. Deletion of SIRPα in podocytes exacerbates, while transgenic overexpression of SIRPα alleviates, podocyte injury in experimental DN mice. Mechanistically, SIRPα downregulation promotes pyruvate kinase M2 (PKM2) phosphorylation, initiating a positive feedback loop that involves PKM2 nuclear translocation, NF-κB activation, and oxidative stress, ultimately impairing aerobic glycolysis. Consistent with this mechanism, shikonin ameliorates podocyte injury by reducing PKM2 nuclear translocation, preventing oxidative stress and NF-κB activation, thereby restoring aerobic glycolysis.

Lipid-lowering drugs, especially statins, are extensively utilized in clinical settings for the prevention of hyperlipidemia. Nevertheless, prolonged usage of current lipid-lowering medications is associated with significant adverse reactions. Therefore, it is imperative to develop novel therapeutic agents for lipid-lowering therapy. In this study, a chenodeoxycholic acid and lactobionic acid double-modified polyethyleneimine (PDL) nanocomposite as a gene delivery vehicle for lipid-lowering therapy by targeting the liver, are synthesized. Results from the in vitro experiments demonstrate that PDL exhibits superior transfection efficiency compared to polyethyleneimine in alpha mouse liver 12 (AML12) cells and effectively carries plasmids. Moreover, PDL can be internalized by AML12 cells and rapidly escape lysosomal entrapment. Intravenous administration of cyanine5.5 (Cy5.5)-conjugated PDL nanocomposites reveals their preferential accumulation in the liver compared to polyethyleneimine counterparts. Systemic delivery of low-density lipoprotein receptor plasmid-loaded PDL nanocomposites into mice leads to reduced levels of low-density lipoprotein cholesterol (LDL-C) and triglycerides (TC) in the bloodstream without any observed adverse effects on mouse health or well-being. Collectively, these findings suggest that low-density lipoprotein receptor plasmid-loaded PDL nanocomposites hold promise as potential therapeutics for lipid-lowering therapy.

BACKGROUND:Long-term accumulation of misfolded proteins leads to endoplasmic reticulum (ER) stress in colorectal cancer (CRC). However, the precise pathways controlling the decision between survival and apoptosis in CRC are unclear. Therefore, in this study, we investigated the function and molecular mechanism of glucosidase I (GCS1) in regulating ER stress in CRC. METHODS:A public database was used to confirm the expression level of GCS1 in CRC and normal tissues. Clinical samples from our center were used to confirm the mRNA and protein expression levels of GCS1. Cell proliferation, migration, invasion, and apoptosis assays revealed the biological role of GCS1. Immunohistochemical techniques were used to evaluate the expression of key proteins in subcutaneous implanted tumors in nude mice, which provided further evidence for the biological function of GCS1 in promoting cancer in vivo. The results of coimmunoprecipitation-mass spectrometry analysis and immunofluorescence colocalization analysis the interaction between GCS1 and GRP78. In addition, the mechanism of action of USP10, GRP78, and GCS1 at the post- translational level was investigated. Finally, a tissue microarray was used to examine the connection between GCS1 and GRP78 expression and intracellular localization of these proteins using immunohistochemistry and immunofluorescence. RESULTS:The experimental results revealed that GCS1 was substantially expressed in CRC, with higher expression indicating a worse prognosis. Thus, GCS1 can enhance the proliferation and metastasis while inhibiting the apoptosis of CRC cells both in vivo and in vitro. Mechanistically, GCS1 binds to GRP78, recruits USP10 for deubiquitination of GRP78 to promote its degradation, and decreases ER stress-mediated apoptosis, increasing CRC cell proliferation and metastasis. CONCLUSIONS:In summary, GCS1 stimulates CRC growth and migration and reduces ER stress-mediated apoptosis via USP10-mediated deubiquitination of GRP78. Our findings identify a possible therapeutic target for CRC.

BackgroundAerobic glycolysis is a process that metabolizes glucose under aerobic conditions, finally producing pyruvate, lactic acid, and ATP for tumor cells. Nevertheless, the overall significance of glycolysis-related genes in colorectal cancer and how they affect the immune microenvironment have not been investigated. MethodsBy combining the transcriptome and single-cell analysis, we summarize the various expression patterns of glycolysis-related genes in colorectal cancer. Three glycolysis-associated clusters (GAC) were identified with distinct clinical, genomic, and tumor microenvironment (TME). By mapping GAC to single-cell RNA sequencing analysis (scRNA-seq), we next discovered that the immune infiltration profile of GACs was similar to that of bulk RNA sequencing analysis (bulk RNA-seq). In order to determine the kind of GAC for each sample, we developed the GAC predictor using markers of single cells and GACs that were most pertinent to clinical prognostic indications. Additionally, potential drugs for each GAC were discovered using different algorithms. ResultsGAC1 was comparable to the immune-desert type, with a low mutation probability and a relatively general prognosis; GAC2 was more likely to be immune-inflamed/excluded, with more immunosuppressive cells and stromal components, which also carried the risk of the poorest prognosis; Similar to the immune-activated type, GAC3 had a high mutation rate, more active immune cells, and excellent therapeutic potential. ConclusionIn conclusion, we combined transcriptome and single-cell data to identify new molecular subtypes using glycolysis-related genes in colorectal cancer based on machine-learning methods, which provided therapeutic direction for colorectal patients.

Background: Lysosomes are essential for the development and recurrence of cancer. The relationship between a single lysosome-related gene and cancer has previously been studied, but the relationship between the lysosome-related genes (LRGs) and colon adenocarcinoma (COAD) remains unknown. This research examined the role of lysosome-related genes in colon adenocarcinoma.Methods: 28 lysosome-related genes associated with prognosis (PLRGs) were found by fusing the gene set that is differently expressed between tumor and non-tumor in colon adenocarcinoma with the gene set that is related to lysosomes. Using consensus unsupervised clustering of PLRGs, the colon adenocarcinoma cohort was divided into two subtypes. Prognostic and tumor microenvironment (TME) comparisons between the two subtypes were then made. The PLRGs_score was constructed using the least absolute shrinkage and selection operator regression (LASSO) method to quantify each patient's prognosis and provide advice for treatment. Lastly, Western Blot and immunohistochemistry (IHC) were used to identify MOGS expression at the protein level in colon adenocarcinoma tissues.Results: PLRGs had more somatic mutations and changes in genetic level, and the outcomes of the two subtypes differed significantly in terms of prognosis, tumor microenvironment, and enrichment pathways. Then, PLRGs_score was established based on two clusters of differential genes in the cancer genome atlas (TCGA) database, and external verification was performed using the gene expression omnibus (GEO) database. Then, we developed a highly accurate nomogram to enhance the clinical applicability of the PLRGs_score. Finally, a higher PLRGs_score was associated with a poorer overall survival (OS), a lower tumor mutation burden (TMB), a lower cancer stem cell (CSC) index, more microsatellite stability (MSS), and a higher clinical stage. MOGS was substantially elevated at the protein level in colon adenocarcinoma as additional confirmation.Conclusion: Overall, based on PLRGs, we identified two subtypes that varied significantly in terms of prognosis and tumor microenvironment. Then, in order to forecast patient prognosis and make treatment suggestions, we developed a diagnostic model with major significance for prognosis, clinical relevance, and immunotherapy. Moreover, we were the first to demonstrate that MOGS is highly expressed in colon adenocarcinoma.

Mono-methylation of histone H3 on Lys 4 (H3K4me1), which is catalyzed by histone-lysine N-methyltransferase 2D (KMT2D), serves as an important epigenetic regulator in transcriptional control. In this study, the authors identify early B-cell factor 2 (EBF2) as a binding protein of H3K4me1. Combining analyses of RNA-seq and ChIP-seq data, the authors further identify killin (KLLN) as a transcriptional target of KMT2D and EBF2 in pancreatic ductal adenocarcinoma (PDAC) cells. KMT2D-dependent H3K4me1 and EBF2 are predominantly over-lapped proximal to the transcription start site (TSS) of KLLN gene. Comprehensive functional assays show that KMT2D and EBF2 cooperatively inhibit PDAC cells proliferation, migration, and invasion through upregulating KLLN. Such inhibition on PDAC progression is also achieved through increasing H3K4me1 level by GSK-LSD1, a selective inhibitor of lysine-specific demethylase 1 (LSD1). Taken together, these findings reveal a new mechanism underlying PDAC progression and provide potential therapeutic targets for PDAC treatment.