Histone 3 lysine-27 demethylase KDM6A coordinates with KMT2B to play an oncogenic role in NSCLC by regulating H3K4me3

Leng, Xuejiao; Wang, Jianfeng; An, Na; Wang, Xue; Sun, Yile; Chen, Zhiwei

doi:10.1038/s41388-020-01449-y

Cited by 25 publications

(26 citation statements)

References 39 publications

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“…Clinically, a high level of MLL2 is significantly associated with early-stage ESCC lymph node metastasis [34]. Knockdown of MLL2 and KDM6A in NSCLC cell lines markedly inhibited the tumorigenic phenotype both in vitro and in vivo [35]. In this study, MLL2 knockdown also significantly inhibited the proliferation of lung cancer cells ( Figure 4D) and downregulated positive cell cycle regulators ( Figure 4E,F).…”

Section: Discussionsupporting

confidence: 56%

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

Kim

Lee

et al. 2021

Cancers

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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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Section: Discussionsupporting

confidence: 56%

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

Kim

Lee

et al. 2021

Cancers

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“…For examples, UTX loss is a driver of bladder cancer (Nickerson et al 2014); UTX cooperates with MLL4 to promote cell proliferation and invasiveness in breast cancer (Kim et al 2014); while another study reports that UTX inhibits breast cancer stem cell properties, suggesting its tumor surpressing role (Choi et al 2015). Similarly, UTX played a different role in NSCLC, acting as a tumor suppressor in some parts of NSCLC and as an oncogene in other parts (Leng et al 2020;Wu et al 2018). As for how to classify the subtypes of NSCLC according to the function of UTX, it is worthwhile for us to continue our exploration.…”

Section: Discussionmentioning

confidence: 99%

EGFR transcriptionally upregulates UTX via STAT3 in non-small cell lung cancer

Zhou

Wang

et al. 2021

J Cancer Res Clin Oncol

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Background Histone demethylase UTX has been reported to participate in the occurrence and development of many cancers in tissue-specific manners. However, the role of UTX in non-small cell lung cancer (NSCLC) and exactly what regulates the expression of UTX remains unclear. Here, we analyzed the role of UTX in NSCLC in association with the widely recognized tumor driver epidermal growth factor receptor (EGFR). Methods UTX levels in clinical samples were detected by immunohistochemistry staining, western blotting and real-time quantitative PCR. The expression of UTX in tumor tissue was correlated with the phosphorylation of EGFR. Cell proliferation and migration were evaluated by MTT and wound-healing assays. The impact of EGFR and its downstream pathways on UTX was explored with corresponding inhibitors, and examined by western blotting and real-time quantitative PCR. Results In this study, we found that the expression of UTX in cancer tissues of patients with NSCLC was significantly higher than that in paracancerous tissues, and positively associated with EGFR phosphorylation levels. In addition, in NSCLC cell lines, UTX can promote proliferation and migration, while inhibition of its enzyme activity suppressed cell growth. Moreover, UTX expression was significantly upregulated when EGFR signaling pathway was activated, and vice versa when EGFR pathway was inhibited by tyrosine kinase inhibitor. Further mechanistic studies suggested that the activation of EGFR activated its downstream JAK/STAT3 signaling pathway and promoted STAT3 phosphorylation; the phosphorylated STAT3 transcriptionally promoted the levels of UTX. Conclusions These results suggest an “EGFR-STAT3-UTX” axis that plays an oncogenic role in NSCLC.

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“…In a study by Lv BB et al, increased methylation of H3K4me3 has been reported to be associated with the activation of the MDM2-p21-E2F1 axis [ 38 ]. On the other hand, KDM2B-mediated demethylation of H3K4me3, along with KDM6A-mediated demethylation of H3K27me3, has been found to promote EZH2 expression and the subsequent progression of non-small cell lung cancer [ 39 ]. Likewise, a similar KDM2B-H3K4me3-mediated EZH2 upregulation has been found in ovarian cancer cells [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

Oncogenic role of ALX3 in cervical cancer cells through KDM2B-mediated histone demethylation of CDC25A

Zhou

et al. 2021

BMC Cancer

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Background Cell division cycle 25A (CDC25A) is a well-recognized regulator of cell cycle progression and is involved in cancer development. This work focused on the function of CDC25A in cervical cancer cell growth and the molecules involved. Methods A GEO dataset GSE63514 comprising data of cervical squamous cell carcinoma (CSCC) tissues was used to screen the aberrantly expressed genes in cervical cancer. The CDC25A expression in cancer and normal tissues was predicted in the GEPIA database and that in CSCC and normal cells was determined by RT-qPCR and western blot assays. Downregulation of CDC25A was introduced in CSCC cells to explore its function in cell growth and the cell cycle progression. The potential regulators of CDC25A activity and the possible involved signaling were explored. Results CDC25A was predicted to be overexpressed in CSCC, and high expression of CDC25A was observed in CSCC cells. Downregulation of CDC25A in ME180 and C33A cells reduced cell proliferation and blocked cell cycle progression, and it increased cell apoptosis. ALX3 was a positive regulator of CDC25A through transcription promotion. It recruited a histone demethylase, lysine demethylase 2B (KDM2B), to the CDC25A promoter, which enhanced CDC25A expression through demethylation of H3k4me3. Overexpression of ALX3 in cells blocked the inhibitory effects of CDC25A silencing. CDC25A was found as a positive regulator of the PI3K/Akt signaling pathway. Conclusion This study suggested that the ALX3 increased CDC25A expression through KDM2B-mediated demethylation of H3K4me3, which induced proliferation and cell cycle progression of cervical cancer cells.

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Histone 3 lysine-27 demethylase KDM6A coordinates with KMT2B to play an oncogenic role in NSCLC by regulating H3K4me3

Cited by 25 publications

References 39 publications

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

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

EGFR transcriptionally upregulates UTX via STAT3 in non-small cell lung cancer

Oncogenic role of ALX3 in cervical cancer cells through KDM2B-mediated histone demethylation of CDC25A

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