Metformin Reduces Histone H3K4me3 at the Promoter Regions of Positive Cell Cycle Regulatory Genes in Lung Cancer Cells

Abstract BackgroundThis study aimed at understanding the effect of metformin on histone H3 modifications at the promoters of cell cycle regulatory genes in lung cancer cells. MethodsHistone H3 modifications were analyzed using ChIP-seq, and changes in DNA methylation and chromatin accessibility were evaluated using the SureSelect Methyl-Seq Target Enrichment System and ATAC-seq, respectively. MLL2 overexpression was analyzed in tumor and matched normal tissues from 42 non-small cell lung cancer (NSCLC) patients. ResultsMetformin showed little effect on DNA methylation or chromatin accessibility at the promoter regions of cell cycle regulatory genes in lung cancer cells but significantly downregulated histone H3K4 methyltransferase MLL2 and reduced H3K4me3 levels at the promoters of positive cell cycle regulatory genes such as CDK1, CDK6, and E2F8. Eighty-eight genes involved in cell cycle showed reduced H3K4me3 levels in response to metformin, and 27% of them showed mRNA downregulation. The siRNA-mediated knockdown of MLL2 significantly reduced the H3K4me3 levels at the promoters of positive cell cycle regulatory genes. MLL2 overexpression was found in 14 (33%) of 42 NSCLC patients, with a higher prevalence in females (P = 0.04). A Cox proportional hazards analysis showed that recurrence-free survival of adenocarcinoma patients with MLL2 overexpression was approximately 1.32 (95% CI = 1.08–4.72; p = 0.02) times poorer than in those without it after adjusting for sex and pathologic stage. ConclusionsThe present study suggests that metformin might reduce H3K4me3 levels at the promoters of positive cell cycle regulatory genes through MLL2 downregulation in lung cancer cells. And, MLL2 may be a potential therapeutic target for reducing the recurrence of lung adenocarcinoma.

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Metformin Reduces Histone H3K4me3 at the Promoter Regions of Positive Cell Cycle Regulatory Genes in Lung Cancer Cells

Cancers ◽

10.3390/cancers13040739 ◽

2021 ◽

Vol 13 (4) ◽

pp. 739

Author(s):

Dongho Kim ◽

Yujin Kim ◽

Bo Bin Lee ◽

Eun Yoon Cho ◽

Joungho Han ◽

...

Keyword(s):

Lung Cancer ◽

Cell Cycle ◽

Dna Methylation ◽

Lung Adenocarcinoma ◽

Cancer Cells ◽

Chromatin Accessibility ◽

Regulatory Genes ◽

Lung Cancer Cells ◽

Promoter Regions ◽

Cell Cycle Regulatory Genes

This study aimed at understanding the effect of metformin on histone H3 methylation, DNA methylation, and chromatin accessibility in lung cancer cells. Metformin significantly reduced H3K4me3 level at the promoters of positive cell cycle regulatory genes such as CCNB2, CDK1, CDK6, and E2F8. Eighty-eight genes involved in cell cycle showed reduced H3K4me3 levels in response to metformin, and 27% of them showed mRNA downregulation. Metformin suppressed the expression of H3K4 methyltransferases MLL1, MLL2, and WDR82. The siRNA-mediated knockdown of MLL2 significantly downregulated global H3K4me3 level and inhibited lung cancer cell proliferation. MLL2 overexpression was found in 14 (33%) of 42 NSCLC patients, and a Cox proportional hazards analysis showed that recurrence-free survival of lung adenocarcinoma patients with MLL2 overexpression was approximately 1.32 (95% CI = 1.08–4.72; p = 0.02) times poorer than in those without it. Metformin showed little effect on DNA methylation and chromatin accessibility at the promoter regions of cell cycle regulatory genes. The present study suggests that metformin reduces H3K4me3 levels at the promoters of positive cell cycle regulatory genes through MLL2 downregulation in lung cancer cells. Additionally, MLL2 may be a potential therapeutic target for reducing the recurrence of lung adenocarcinoma.

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Overexpression of cyclin L2 induces apoptosis and cell-cycle arrest in human lung cancer cells

Chinese Medical Journal ◽

10.1097/00029330-200705020-00010 ◽

2007 ◽

Vol 120 (10) ◽

pp. 905-909 ◽

Cited By ~ 14

Author(s):

Hong-li LI ◽

Tong-shan WANG ◽

Xiao-yu LI ◽

Nan LI ◽

Ding-zhi HUANG ◽

...

Keyword(s):

Lung Cancer ◽

Cell Cycle ◽

Cell Cycle Arrest ◽

Cancer Cells ◽

Human Lung ◽

Lung Cancer Cells ◽

Human Lung Cancer ◽

Cycle Arrest ◽

Human Lung Cancer Cells

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Antiproliferative Activity and Potential Mechanism of Marine-Sourced Streptoglutarimide H against Lung Cancer Cells

Marine Drugs ◽

10.3390/md19020079 ◽

2021 ◽

Vol 19 (2) ◽

pp. 79

Author(s):

Hengju Ge ◽

Di Zhang ◽

Muran Shi ◽

Xiaoyuan Lian ◽

Zhizhen Zhang

Keyword(s):

Lung Cancer ◽

Cell Cycle ◽

Cancer Cells ◽

Antiproliferative Activity ◽

Lung Cancer Cells ◽

Potential Mechanism ◽

Nucleotide Synthesis ◽

Factor C ◽

Antiglioma Activity

In 2019, streptoglutarimide H (SGH) was characterized as a new glutarimide from the secondary metabolites produced by a marine-derived actinomycete Streptomyces sp. ZZ741 and shown to have in vitro antiglioma activity. However, the antiproliferative activity and potential mechanism of SGH against lung cancer cells have not yet been characterized. This study demonstrated that SGH significantly inhibited the proliferation of different lung cancer cells. In terms of mechanism of action, SGH downregulated cell cycle- and nucleotide synthesis-related proteins to block cell cycle at G0/G1 phase, reduced the expression levels of glycolytic metabolic enzymes to inhibit glycolysis, and downregulated the important cancer transcription factor c-Myc and the therapeutic target deubiquitinase USP28. Potent anticancer activity and multiple mechanisms indicated SGH to be a novel antitumor compound against lung cancer cells.

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Disruption of SHH signaling cascade by SBE attenuates lung cancer progression and sensitizes DDP treatment

Scientific Reports ◽

10.1038/s41598-017-02063-x ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 8

Author(s):

Jing Du ◽

Weiwei Chen ◽

Lijuan Yang ◽

Juanjuan Dai ◽

Jiwei Guo ◽

...

Keyword(s):

Lung Cancer ◽

Cell Cycle ◽

Cancer Cells ◽

Signaling Pathway ◽

Cell Cycle Progression ◽

Lung Cancer Cells ◽

Human Lung Cancer ◽

Cycle Progression ◽

Shh Signaling ◽

Shh Pathway

Abstract Deregulated Sonic Hedgehog (SHH) pathway facilitates the initiation, progression, and metastasis of Non-small cell lung cancer (NSCLC), confers drug resistance and renders a therapeutic interference option to lung cancer patients with poor prognosis. In this study, we screened and evaluated the specificity of a Chinese herb Scutellariabarbata D. Don extraction (SBE) in repressing SHH signaling pathway to block NSCLC progression. Our study confirmed that aberrant activation of the SHH signal pathway conferred more proliferative and invasive phenotypes to human lung cancer cells. This study revealed that SBE specifically repressed SHH signaling pathway to interfere the SHH-mediated NSCLC progression and metastasis via arresting cell cycle progression. We also found that SBE significantly sensitized lung cancer cells to chemotherapeutic agent DDP via repressing SHH components in vitro and in vivo. Mechanistic investigations indicated that SBE transcriptionally and specifically downregulated SMO and consequently attenuated the activities of GLI1 and its downstream targets in SHH signaling pathway, which interacted with cell cycle checkpoint enzymes to arrest cell cycle progression and lead to cellular growth inhibition and migration blockade. Collectively, our results suggest SBE as a novel drug candidate for NSCLC which specifically and sensitively targets SHH signaling pathway.

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Loss of asparagine synthetase suppresses the growth of human lung cancer cells by arresting cell cycle at G0/G1 phase

Cancer Gene Therapy ◽

10.1038/cgt.2016.28 ◽

2016 ◽

Vol 23 (9) ◽

pp. 287-294 ◽

Cited By ~ 13

Author(s):

Yi Xu ◽

Fanzhen Lv ◽

Xunxia Zhu ◽

Yun Wu ◽

Xiaoyong Shen

Keyword(s):

Lung Cancer ◽

Cell Cycle ◽

Cancer Cells ◽

Human Lung ◽

Asparagine Synthetase ◽

Lung Cancer Cells ◽

Human Lung Cancer ◽

G1 Phase ◽

Human Lung Cancer Cells

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STIP overexpression confers oncogenic potential to human non‐small cell lung cancer cells by regulating cell cycle and apoptosis

Journal of Cellular and Molecular Medicine ◽

10.1111/jcmm.12670 ◽

2015 ◽

Vol 19 (12) ◽

pp. 2806-2817 ◽

Cited By ~ 5

Author(s):

Yani Tang ◽

Guobei Yan ◽

Xin Song ◽

Kuangpei Wu ◽

Zhen Li ◽

...

Keyword(s):

Lung Cancer ◽

Cell Cycle ◽

Small Cell Lung Cancer ◽

Cancer Cells ◽

Cell Lung Cancer ◽

Small Cell ◽

Lung Cancer Cells ◽

Small Cell Lung ◽

Oncogenic Potential

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Identification of potential pathways involved in the induction of cell cycle arrest and apoptosis by a new 4-arylidene curcumin analogue T63 in lung cancer cells: a comparative proteomic analysis

Molecular BioSystems ◽

10.1039/c3mb70553f ◽

2014 ◽

Vol 10 (6) ◽

pp. 1320 ◽

Cited By ~ 18

Author(s):

Hao Liu ◽

Yan-Zhen Liu ◽

Fan Zhang ◽

Hong-Sheng Wang ◽

Ge Zhang ◽

...

Keyword(s):

Lung Cancer ◽

Cell Cycle ◽

Cell Cycle Arrest ◽

Cancer Cells ◽

Proteomic Analysis ◽

Lung Cancer Cells ◽

Comparative Proteomic Analysis ◽

Curcumin Analogue ◽

Cycle Arrest

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10-HDA Induces ROS-Mediated Apoptosis in A549 Human Lung Cancer Cells by Regulating the MAPK, STAT3, NF-κB, and TGF-β1 Signaling Pathways

BioMed Research International ◽

10.1155/2020/3042636 ◽

2020 ◽

Vol 2020 ◽

pp. 1-15

Author(s):

Xin-Mei Lin ◽

Shao-Bin Liu ◽

Ying-Hua Luo ◽

Wan-Ting Xu ◽

Yu Zhang ◽

...

Keyword(s):

Lung Cancer ◽

Cell Cycle ◽

Cancer Cells ◽

Signaling Pathways ◽

Human Lung ◽

Lung Cancer Cells ◽

Human Lung Cancer ◽

Cycle Arrest ◽

Human Lung Cancer Cells ◽

Tgf Β1

10-Hydroxy-2-decenoic acid (10-HDA), also known as royal jelly acid, has a variety of physiological functions, and recent studies have shown that it also has anticancer effects. However, its anticancer mechanisms have not been clearly defined. In this study, we investigated the underlying mechanisms of 10-HDA in A549 human lung cancer cells. We used Cell Counting Kit-8 assay, scratch wound healing assay, flow cytometry, and western blot analysis to investigate its apoptotic effects and underlying mechanism. Our results showed that 10-HDA inhibited the proliferation of three types of human lung cancer cells and had no significant toxic effects on normal cells. Accompanying reactive oxygen species (ROS), 10-HDA induced A549 cell apoptosis by regulating mitochondrial-associated apoptosis, and caused cell cycle arrest at the G0/G1 phase in a time-dependent manner. Meanwhile, 10-HDA also regulated mitogen-activated protein kinase (MAPK), signal transducer and activator of transcription 3 (STAT3), and nuclear factor kappa B (NF-κB) signaling pathways by increasing the expression levels of phosphorylated c-Jun N-terminal kinase, p-p38, and I-κB, and additionally, by decreasing the expression levels of phosphorylated extracellular signal-regulated kinase, p-STAT3, and NF-κB. These effects were blocked by MAPK inhibitors and N-acetyl-L-cysteine. Furthermore, 10-HDA inhibited cell migration by regulating transforming growth factor beta 1 (TGF-β1), SNAI1, GSK-3β, E-cadherin, N-cadherin, and vimentin. Taken together, the results of this study showed that 10-HDA induced cell cycle arrest and apoptosis in A549 human lung cancer cells through ROS-mediated MAPK, STAT3, NF-κB, and TGF-β1 signaling pathways. Therefore, 10-HDA may be a potential therapy for human lung cancer.

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