Epigenetic alterations my play a role in the aggressive behavior of Non-Small Cell Lung Cancer (NSCLC). Treatment with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA, vorinostat) has been reported to interfere with the proliferative and invasive potential of NSCLC cells. In addition, the DNA methyltransferase inhibitor azacytidine (AZA, vidaza) can modulate the levels of the metastasis suppressor KiSS-1. Thus, since cisplatin is still clinically available for NSCLC therapy, the aim of this study was to evaluate drug combinations between cisplatin and SAHA as well as AZA using cisplatin-sensitive H460 and -resistant H460/Pt NSCLC cells in relation to KiSS-1 modulation. An analysis of drug interaction according to the Combination-Index values indicated a more marked synergistic effect when the exposure to SAHA or AZA preceded cisplatin treatment with respect to a simultaneous schedule. A modulation of proteins involved in apoptosis (p53, Bax) was found in both sensitive and resistant cells, and compared to the treatment with epigenetic agents alone, the combination of cisplatin and SAHA or AZA increased apoptosis induction. The epigenetic treatments, both as single agents and in combination, increased the release of KiSS-1. Finally, the exposure of cisplatin-sensitive and -resistant cells to the kisspeptin KP10 enhanced cisplatin induced cell death. The efficacy of the combination of SAHA and cisplatin was tested in vivo after subcutaneous inoculum of parental and resistant cells in immunodeficient mice. A significant tumor volume inhibition was found when mice bearing advanced tumors were treated with the combination of SAHA and cisplatin according to the best schedule identified in cellular studies. These results, together with the available literature, support that epigenetic drugs are amenable for the combination treatment of NSCLC, including patients bearing cisplatin-resistant tumors.

Inflammation and thrombosis are two distinct yet interdependent physiological processes. The inflammation results in the activation of the coagulation system that directs the immune system and its activation, resulting in the initiation of the pathophysiology of thrombosis, a process termed immune-thrombosis. Still, the shared underlying molecular mechanism related to the immune system and coagulation has not yet been explored extensively. Inspired to answer this, we carried out a comprehensive gene expression meta-analysis using publicly available datasets of four diseases, including venous thrombosis, systemic lupus erythematosus, rheumatoid arthritis, and inflammatory bowel disease. A total of 609 differentially expressed genes (DEGs) shared by all four datasets were identified based on the combined effect size approach. The pathway enrichment analysis of the DEGs showed enrichment of various epigenetic pathways such as histone-modifying enzymes, posttranslational protein modification, chromatin organization, chromatin-modifying enzymes, HATs acetylate proteins. Network-based protein-protein interaction analysis showed epigenetic enzyme coding genes dominating among the top hub genes. The miRNA-interacting partner of the top 10 hub genes was determined. The predomination of epitranscriptomics regulation opens a layout for the meta-analysis of miRNA datasets of the same four diseases. We identified 30 DEmiRs shared by these diseases. There were 9 common DEmiRs selected from the list of miRNA-interacting partners of top 10 hub genes and shared significant DEmiRs from microRNAs dataset acquisition. These common DEmiRs were found to regulate genes involved in epigenetic modulation and indicate a promising epigenetic aspect that needs to be explored for future molecular studies in the context of immunothrombosis and inflammatory disease.

UNASSIGNED: Epigenetic mechanisms play vital roles in the activation, differentiation, and effector function of immune cells. The breast and kidney-expressed chemokine (CXCL14) mainly contributes to the regulation of immune cells. However, its role in shaping the tumor immune microenvironment (TIME) is yet to be elucidated in renal cell carcinoma (RCC).
UNASSIGNED: This study aimed to elucidate the role of CXCL14 in predicting the efficacy of immunotherapy in patients with RCC.
UNASSIGNED: CXCL14 expression and RNA-sequencing, single-cell RNA-sequencing (scRNA-seq), and survival datasets of RCC from public databases were analyzed, and survival was compared between different CXCL14 levels. The correlation between CXCL14 and immune infiltration and human leukocyte antigen (HLA) gene expression was analyzed with TIMER2.0 and gene expression profiling interactive analysis. Institutional scRNA-seq and immunohistochemical staining analyses were used to verify the relationship between CXCL14 expression level and the efficacy of immunotherapy.
UNASSIGNED: CXCL14 was expressed in fibroblast and malignant cells in RCC, and higher expression was associated with better survival. Enrichment analysis revealed that CXCL14 is involved in immune activation, primarily in antigen procession, antigen presentation, and major histocompatibility complex assemble. CXCL14 expression was positively correlated with T-cell infiltration as well as HLA-related gene expression. Among the RCC cohort receiving nivolumab in Checkmate 025, the patients with CXCL14 high expression had better overall survival than those with CXCL14 low expression after immunotherapy. scRNA-seq revealed a cluster of CXCL14+ fibroblast in immunotherapy responders. Immunohistochemistry analysis verified that the patients with high CXCL14 expression had an increased proportion of high CD8 expression simultaneously. The expression level of CXCL14 was associated with CXCR4 expression in RCC.
UNASSIGNED: CXCL14 expression is associated with immunotherapy response in RCC. It is a promising biomarker for immunotherapy response prediction and may be an effective epigenetic modulator in combination with immunotherapy approaches.
CXCL14 as potential predictor for immunotherapy response in kidney cancer Kidney-expressed chemokine (CXCL14) regulates immune cells. We studied how it affects the body’s immune response to kidney cancer based on public and private database and staining. We found that higher levels of CXCL14 in kidney cancer were linked to better patient survival. CXCL14 seems to help activate the immune system. When patients with high CXCL14 levels received immunotherapy, they tended to survive longer than those with low levels. Fibroblasts with CXCL14 were present in patients responding to immunotherapy. Further tests confirmed that high CXCL14 levels were related to more immune cells. CXCR4 may be its receptor in kidney cancer. This suggests that measuring CXCL14 levels could help predict how well a patient might respond to immunotherapy for kidney cancer.

Breast cancer is a heterogeneous disease and a leading malignancy around the world. It is a vital cause of untimely mortality among women. Drug resistance is the major challenge for effective cancer therapeutics. In contrast, cancer stem cells (CSCs) are one of the reasons for drug resistance, tumor progression, and metastasis. The small population of CSCs present in each tumor has the ability of self-renewal, differentiation, and tumorigenicity. CSCs are often identified and enriched using a variety of cell surface markers (CD44, CD24, CD133, ABCG2, CD49f, LGR5, SSEA-3, CD70) that exert their functions by different regulatory networks, i.e., Notch, Wnt/β-catenin, hedgehog (Hh), and Hippo signaling pathways. Particularly the Hippo signaling pathway is the emerging and very less explored cancer stem cell pathway. Here, in this review, the Hippo signaling molecules are elaborated with respect to their ability of stemness as epigenetic modulators and how these molecules can be targeted for better cancer treatment and to overcome drug resistance.

Small molecules have enabled expansion of hematopoietic stem and progenitor cells (HSPCs), but limited knowledge is available on whether these agonists can act synergistically. In this work, we identify a stem cell agonist in AA2P and optimize a series of stem cell agonist cocktails (SCACs) to help promote robust expansion of human HSPCs. We find that SCACs provide strong growth-promoting activities while promoting retention and function of immature HSPC. We show that AA2P-mediated HSPC expansion is driven through DNA demethylation leading to enhanced expression of AXL and GAS6. Further, we demonstrate that GAS6 enhances the serial engraftment activity of HSPCs and show that the GAS6/AXL pathway is critical for robust HSPC expansion.

The development of malignant tumors is caused by a complex combination of genetic mutations and epigenetic alterations, the latter of which are induced by either external environmental factors or signaling disruption following genetic mutations. Some types of cancer demonstrate a significant increase in epigenetic enzymes, and targeting these epigenetic alterations represents a compelling strategy to reverse cell transcriptome to the normal state, improving chemotherapy response. Curaxin CBL0137 is a new potent anticancer drug that has been shown to activate epigenetically silenced genes. However, its detailed effects on the enzymes of the epigenetic system of transcription regulation have not been studied. Here, we report that CBL0137 inhibits the expression of DNA methyltransferase DNMT3a in HeLa TI cells, both at the level of mRNA and protein, and it decreases the level of integral DNA methylation in Ca Ski cells. For the first time, it is shown that CBL0137 decreases the level of BET family proteins, BRD2, BRD3, and BRD4, the key participants in transcription elongation, followed by the corresponding gene expression enhancement. Furthermore, we demonstrate that CBL0137 does not affect the mechanisms of histone acetylation and methylation. The ability of CBL0137 to suppress DNMT3A and BET family proteins should be taken into consideration when combined chemotherapy is applied. Our data demonstrate the potential of CBL0137 to be used in the therapy of tumors with corresponding aberrant epigenetic profiles.

Small cell lung cancer is an aggressive subtype of lung cancer with limited treatment options. Precision medicine has revolutionized cancer treatment for many tumor types but progress in SCLC has been slower due to the lack of targetable biomarkers. This review article provides an overview of emerging strategies for precision therapy in SCLC. Targeted therapies include targeted kinase inhibitors, monoclonal antibodies, angiogenesis inhibitors, antibody-drug conjugates, PARP inhibitors, and epigenetic modulators. Angiogenesis inhibitors and DNA-damaging agents, such as PARP and ATR inhibitors, have been explored in SCLC with limited success to date although trials are ongoing. The potential of targeting DLL3, a NOTCH ligand, through antibody-drug conjugates, bispecific T-cell engagers, and CAR T-cell therapy, has opened up new therapeutic options moving forward. Additionally, new research in epigenetic therapeutics in reversing transcriptional repression, modulating anti-tumor immunity, and utilizing antibody-drug conjugates to target cell surface-specific targets in SCLC are also being investigated. While progress in precision therapy for SCLC has been challenging, recent advancements provide optimism for improved treatment outcomes. However, several challenges remain and will need to be addressed, including drug resistance and tumor heterogeneity. Further research and biomarker-selected clinical trials are necessary to develop effective precision therapies for SCLC patients.

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Activation of oncogenes to sustain proliferative signaling and initiate metastasis are important hallmarks of cancer. Oncogenes are amplified or overexpressed in cancer cells and overexpression is often controlled at the level of transcription. Gene expression is tightly controlled by many cis-regulatory elements and trans-acting factors. Large clusters of enhancers known as \"super-enhancers\" drive robust expression of cell-fate determining transcription factors in cell identity. Cancer cells can take advantage of super-enhancers and become transcriptionally addicted to them leading to tumorigenesis and metastasis. Additionally, the cis-regulatory landscape of cancer includes aberrant super-enhancers that are not present in normal cells. The landscape of super-enhancers in cancer is characterized by high levels of histone H3K27 acetylation and bromodomain-containing protein 4 (BRD4), and Mediator complex. These chromatin features facilitate the identification of cancer type-specific and cell-type-specific super-enhancers that control the expression of important oncogenes to stimulate their growth. Disruption of super-enhancers via inhibiting BRD4 or other epigenetic proteins is a potential therapeutic option. Here, we will describe the discovery of super-enhancers and their unique characteristics compared to typical enhancers. Then, we will highlight how super-enhancer-associated genes contribute to cancer progression in different solid tumor types. Lastly, we will cover therapeutic targets and their epigenetic modulators.

The accumulation of cell biomass is associated with dramatically increased bioenergetic and biosynthetic demand. Metabolic reprogramming, once thought as an epiphenomenon, currently relates to disease progression, also in response to extracellular fate-decisive signals. Glioblastoma multiforme patients often suffer misdiagnosis, short survival time, low quality of life, and poor disease management options. Today, tumor genetic testing and histological analysis guide diagnosis and treatment. We and others appreciate that metabolites complement translational biomarkers and molecular signatures in disease profiling and phenotyping. Herein, we coupled a mixed-methods content analysis to a mass spectrometry-based untargeted metabolomic analysis on plasma samples from glioblastoma multiforme patients to delineate the role of metabolic remodeling in biological plasticity and, hence, disease severity. Following data processing and analysis, we established a bioenergetic profile coordinated by the mitochondrial function and redox state, lipids, and energy substrates. Our findings show that epigenetic modulators are key players in glioblastoma multiforme cell metabolism, in particular when microRNAs are considered. We propose that biological plasticity in glioblastoma multiforme is a mechanism of adaptation and resistance to treatment which is eloquently revealed by bioenergetics.