Effect of metformin on mRNA expression in lung cancer cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE141052 | GEO | 2019/11/27
REPOSITORIES: GEO
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Project description:The DNA regions that were associated with the metformin altered expressions of H3K4me3 and/or H3K27me3 were investigated by ChIP-seq, and the regions significantly up- or down-regulated by metformin were identified in H1299 cells. Over 80% of H3K4me3 were discovered within promoter regions, but less than 10% of H3K27me3 were observed in this area. Metformin significantly downregulated H3K4me3 level at the promoter regions of 1113 genes, but upregulated levels in the promoter regions of 1492 genes. Gene enrichment analysis revealed that abundant cell cycle related genes such as PIK3C3, CCNB2, CDK1, CDK6, and E2F8 were upregulated, while certain cell cycle suppressor genes such as CDKN1A (p21) and DDIT4 were downregulated. No specific biological functional cluster was detected in the H3K27me3 up- or downregulated genes.
2019-11-27 | GSE141053 | GEO
Project description:Histone deacetylases (HDACs) are known to be a class of enzymes that remove acetyl groups from lysine chains on histones or other proteins, and play a crucial role in epigenetic regulation and aging process. Previous studies have identified that HDAC4 is down-regulated in aged and UV-irradiated skin in vivo. Therefore, HDAC4 may be an important role in skin aging process. However, the role of HDAC4 in skin aging is rarely known. In this study, we conducted the integrative transcriptome analysis of overexpression and knockdown of HDAC4, and UV- or H2O2-induced senescence in human dermal fibroblast and identified candidate genes which are regulated by HDAC4. Among these genes, DNA damage-inducible transcript 4 (DDIT4) was significantly regulated by HDAC4. We demonstrated that DDIT4 expression was downregulated during senescence and HDAC4 overexpression prevented senescence-induced decrease of DDIT4. In addition, overexpression of DDIT4 reduced SASP and aged-related genes that could promote aging, suggesting that DDIT4 may prevent senescence. Collectively, our results have shown that HDAC4 may play an important role in preventing skin aging by inducing DDIT4 expression.
2021-12-31 | GSE181329 | GEO
Project description:In mouse development, long-term silencing by CpG island DNA methylation is specifically targeted to germline genes, however the molecular mechanisms of this specificity remain unclear. Here we demonstrate that the transcription factor E2F6, a member of the polycomb repressive complex 1.6 (PRC1.6), is critical to target and initiate epigenetic silencing at germline genes in early embryogenesis. Genome-wide, E2F6 binds preferentially to CpG islands in embryonic cells. E2F6 cooperates with MGA to silence a subgroup of germline genes in mouse embryonic stem cells and in vivo, a function that critically depends on the E2F6 marked box domain. Inactivation of E2f6 leads to a failure to deposit CpG island DNA methylation at these genes during implantation. Furthermore, E2F6 is required to initiate epigenetic silencing in early embryonic cells but becomes dispensable for the maintenance in differentiated cells. Our findings elucidate the mechanisms of epigenetic targeting of germline genes and provide a paradigm for how transient repression signals by DNA-binding factors in early embryonic cells are translated into long term epigenetic silencing during mammalian development.
2021-04-22 | PXD023974 | Pride
Project description:Evidence from clinical trials and observational studies suggests that both progressive resistance training (PRT) and metformin delay a variety of age-related morbidities. Previously, we completed a clinical trial testing the effects of 14 weeks of PRT + metformin (metPRT) compared to PRT with placebo (plaPRT) on muscle hypertrophy in older adults. We found that metformin blunted PRT-induced muscle hypertrophic response. To understand potential mechanisms underlying the inhibitory effect of metformin on PRT, we analyzed the muscle transcriptome in 23 metPRT and 24 plaPRT participants. PRT significantly increased expression of genes involved in extracellular matrix remodeling pathways, and downregulated RNA processing pathways in both groups, however, metformin blunted the number of differentially expressed genes within these pathways compared to plaPRT. Pathway analysis showed that genes unique to metPRT modulated aging-relevant pathways, such as cellular senescence and autophagy. Differentially expressed genes from baseline biopsies in older adults compared to resting muscle from young volunteers were reduced following PRT in plaPRT and were further reduced in metPRT. We suggest that although metformin may blunt pathways induced by PRT to promote muscle hypertrophy, adjunctive metformin during PRT may have beneficial effects on aging-associated pathways in muscle from older adults.
2020-09-08 | GSE157585 | GEO
Project description:Metformin is a kind of widely used antidiabetic agent, which regulates glucose homeostasis through inhibiting liver glucose production and increasing glucose uptake in muscle. Recent studies suggest that metformin exhibits anticancer properties in a variety of cancers. Although several antitumor mechanisms have been proposed for metformin action, its mode of action in human liver cancer remains not elucidated. In our study we investigated the underlying molecular mechanisms of metformin’s antitumor effect on Huh-7 cells of hepatocellular carcinoma (HCC) in vitro. RNA sequencing (RNA-seq) was performed to explore the effect of metformin on the transcriptome of Huh-7 cells. The results revealed that 4518 genes (with log2 fold change>1 or < -1, p-adjusted value<0.05) were differentially expressed in Huh-7 cells with treatment of 25mM metformin compared to 0mM metformin including 1812 up-regulated and 2706 down-regulated genes. Gene ontology and KEGG pathway analyses identified 54 classical pathways which were significantly enriched, and 16 pathways are closely associated with cancer, such as cell cycle, DNA replication, ECM-receptor interaction and so on. We selected 11 differentially expressed genes, which are closely associated with HCC to validate their differential expressions through quantitative real-time reverse transcription PCR (qRT-PCR). The result exhibited that the genes of FASN, MCM6, MCM5, MARCKS, FADS2, CXCL1, BMP4, SKP2, KNG1, PCNA were down-regulated and DUSP1 is significantly up-regulated in Huh-7 cells with treatment of 25mM metformin. These differentially expressed genes and pathways might play a crucial part in the antitumor effect of metformin, and might be potential targets of metformin treating HCC. Further investigations are required to evaluate the metformin mechanisms of anti-cancer action in vivo.
2021-12-05 | GSE190076 | GEO
Project description:Metformin shows promise in breast cancer prevention, but its underlying mechanisms remain unclear. This study investigated the impact of metformin on the repopulation dynamics of mammary epithelial cells (MECs) and the signaling pathways in non-tumorigenic FVB/N mice. The mice were treated with metformin for 10 weeks, followed by morphogenesis, flow cytometry, analyses of MEC stemness, and RNA sequencing. The study findings indicated that metformin treatment in adult mice reduced mammary gland proliferation, as demonstrated by decreased Ki67+ cells and lateral bud formation. Additionally, metformin significantly reduced both basal and mammary repopulating unit subpopulations, indicating an impact on mammary epithelial cell repopulation. Mammosphere, colony-forming cell, and 3D culture assays revealed that metformin adversely affected mammary epithelial cell stemness. Furthermore, metformin downregulated signaling in key pathways including AMPK/mTOR, MAPK/Erk, PI3K/Akt, and ER, which contribute to its inhibitory effects on mammary proliferation and stemness. Transcriptome analysis with RNA sequencing indicated that metformin induced significant downregulation of genes involved in multiple critical pathways. KEGG-based pathway analysis indicated that genes in PI3K/Akt, focal adhesion, ECM-receptor, small cell lung cancer and immune-modulation pathways were among the top groups of differentially regulated genes. In summary, our research demonstrates that metformin inhibits MEC proliferation and stemness, accompanied by the downregulation of intrinsic signaling. These insights suggest that the regulatory effects of metformin on premalignant mammary tissues could potentially delay or prevent the onset of breast cancer, offering a promising avenue for developing new preventive strategies.
2024-08-02 | GSE269308 | GEO
Project description:Cell proliferation is tightly controlled by inhibitors that block cell cycle progression until growth signals relieve this inhibition, allowing cells to divide. In several tissues including the liver, cell proliferation is inhibited at mitosis by the transcriptional repressors E2F7 and E2F8, leading to formation of polyploid cells. Whether growth factors promote mitosis and cell cycle progression by relieving the E2F7/E2F8-mediated inhibition is unknown. We report here on a new mechanism of cell division control in the postnatal liver, in which Wnt/βcatenin signaling maintains active hepatocyte cell division through Tbx3, a Wnt target gene. Tbx3 directly represses transcription of E2F7 and E2F8, thereby promoting mitosis. This cascade of sequential transcriptional repressors, initiated by Wnt signals, provides a new paradigm for exploring how commonly active developmental signals impact cell cycle completion.
2022-07-02 | GSE205339 | GEO
Project description:To understand molecular mechanisms underlying the synergy of Rb loss and E2F8 loss, we used gene expression profiling to assess molecular changes in Mx1-Cre-mediated knockout (KO) mice using RNA isolated from sorted Ter119+CD71high Erythroblasts. The top four upregulated and enriched pathways in the DKO mice included DNA replication, DNA damage response, DNA repair, and RNA processing. Interestingly, the majority of upregulated genes in the enriched sections of the four shared pathways contain E2f binding site(s) in their promoters, suggesting that Rb and E2F8 largely repress those genes through the E2f binding sites. Collectively, our data suggest that Rb and E2F8 co-regulate E2F-responsive genes. Spleen Ter119+CD71high cells were sorted from WT, E2f8 KO, Rb KO and E2f8;Rb DKO mice
2014-05-30 | E-GEOD-52157 | biostudies-arrayexpress
Project description:In the mouse, long-term silencing by CpG island DNA methylation is specifically targeted to germline genes in somatic cells, however the molecular mechanisms of this specificity remain unclear. Here we demonstrate that the transcription factor E2F6, a member of the polycomb repressive complex 1.6 (PRC1.6), is critical to target and initiate epigenetic silencing at germline genes in early embryogenesis. Genome-wide, E2F6 binds preferentially to CpG islands in embryonic cells. E2F6 cooperates with MGA to silence a subgroup of germline genes in mouse embryonic stem cells and in vivo, a function that critically depends on the E2F6 marked box domain. Furthermore, inactivation of E2f6 leads to a failure to deposit CpG island DNA methylation at these genes during implantation. Finally, we show that E2F6 is required to initiate epigenetic silencing in early embryonic cells but becomes dispensable for the maintenance in differentiated cells. Our findings elucidate the mechanisms of epigenetic targeting of germline genes and provide a paradigm for how transient repression signals by DNA-binding factors in early embryonic cells are translated into long term epigenetic silencing during mammalian development.
2021-04-26 | GSE149025 | GEO
Project description:Metformin is one of the first-line drugs for clinical treatment of type II diabetes, and recent studies have found that metformin can inhibit the development of multiple malignant tumors. When metformin is combined with chemotherapeutic drugs to treat head and neck squamous cell carcinoma（HNSCC）, it can effectively enhance the efficacy of chemotherapy. The aim of this study was to define the signaling pathways regulated by metformin in HNSCC, and the underlying mechanisms by which metformin sensitizes HNSCC chemotherapy. We used RNA sequencing (RNA-seq) to examine metformin regulated genes in the cal27, human tongue squamous carcinoma cell line, using RT-PCR to determine alterations in gene expression. Data from RNA-seq analysis showed that gene products involved in DNA replication, cell cycle, IL-17 signaling pathway, mismatch repair were all regulated by metformin. Our results suggest that metformin regulates multiple pathways associated with tumor growth and progression in HNSCC.
2022-07-03 | GSE207122 | GEO