G9a and histone deacetylases are crucial for Snail2‐mediated E‐cadherin repression and metastasis in hepatocellular carcinoma

Hu, Yue; Zheng, Yayuan; Dai, Mingrui; Wang, Xueju; Wu, Jiaxin; Yu, Bin; Zhang, Haihong; Cui, Yinqiu; Kong, Wei; Wu, Hui; Yu, Xianghui

doi:10.1111/cas.14173

Cited by 40 publications

(26 citation statements)

References 50 publications

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“…Acetylation of H3K4 and H3K56 within the Snail2 promoter was markedly reduced in EMT thanks to HDAC1 and HDAC3 [ 70 ]. It is worthy to note that G9a, a histone H3 lysine 9 (H3K9) methyltransferase, has been recently recognized as vital for such Snail2 -mediated inhibition of E-cadherin and consequent repression of mesenchymal properties [ 71 ]. It has even been targeted for therapy by administering its inhibitor, UNC0646, in nanodiamonds, which reduced H3K9 methylation and tumor invasiveness [ 72 ].…”

Section: Histone Modificationsmentioning

confidence: 99%

Hepigenetics: A Review of Epigenetic Modulators and Potential Therapies in Hepatocellular Carcinoma

Yousef

El-Fawal

Abdelnaser

2020

BioMed Research International

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Hepatocellular carcinoma is the fifth most common cancer worldwide and the second most lethal, following lung cancer. Currently applied therapeutic practices rely on surgical resection, chemotherapy and radiotherapy, or a combination thereof. These treatment options are associated with extreme adversities, and risk/benefit ratios do not always work in patients’ favor. Anomalies of the epigenome lie at the epicenter of aberrant molecular mechanisms by which the disease develops and progresses. Modulation of these anomalous events poses a promising prospect for alternative treatment options, with an abundance of felicitous results reported in recent years. Herein, the most recent epigenetic modulators in hepatocellular carcinoma are recapitulated on.

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Section: Histone Modificationsmentioning

confidence: 99%

Hepigenetics: A Review of Epigenetic Modulators and Potential Therapies in Hepatocellular Carcinoma

Yousef

El-Fawal

Abdelnaser

2020

BioMed Research International

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“…The dysregulation of G9a and aberrant levels of H3K9me2 are involved in different types of human cancers [12][13][14][15] . As for HCC, G9a promotes tumor progression by silencing tumor suppressor genes or enhancing epithelial-mesenchymal transition 16,17 , and its inhibition reduces tumor aggressiveness 18,19 . In contrast, how G9a contributes to the development or initiation of HCC has not yet been investigated in vivo.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of histone methyltransferase G9a attenuates liver cancer initiation by sensitizing DNA-damaged hepatocytes to p53-induced apoptosis

et al. 2021

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While the significance of acquired genetic abnormalities in the initiation of hepatocellular carcinoma (HCC) has been established, the role of epigenetic modification remains unknown. Here we identified the pivotal role of histone methyltransferase G9a in the DNA damage-triggered initiation of HCC. Using liver-specific G9a-deficient (G9aΔHep) mice, we revealed that loss of G9a significantly attenuated liver tumor initiation caused by diethylnitrosamine (DEN). In addition, pharmacological inhibition of G9a attenuated the DEN-induced initiation of HCC. After treatment with DEN, while the induction of γH2AX and p53 were comparable in the G9aΔHep and wild-type livers, more apoptotic hepatocytes were detected in the G9aΔHep liver. Transcriptome analysis identified Bcl-G, a pro-apoptotic Bcl-2 family member, to be markedly upregulated in the G9aΔHep liver. In human cultured hepatoma cells, a G9a inhibitor, UNC0638, upregulated BCL-G expression and enhanced the apoptotic response after treatment with hydrogen peroxide or irradiation, suggesting an essential role of the G9a-Bcl-G axis in DNA damage response in hepatocytes. The proposed mechanism was that DNA damage stimuli recruited G9a to the p53-responsive element of the Bcl-G gene, resulting in the impaired enrichment of p53 to the region and the attenuation of Bcl-G expression. G9a deletion allowed the recruitment of p53 and upregulated Bcl-G expression. These results demonstrate that G9a allows DNA-damaged hepatocytes to escape p53-induced apoptosis by silencing Bcl-G, which may contribute to the tumor initiation. Therefore, G9a inhibition can be a novel preventive strategy for HCC.

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“…It has been observed that the expression of G9a is upregulated in a number of cancers, including aggressive lung cancer, multiple myeloma, aggressive ovarian carcinoma, brain cancer, hepatocellular carcinoma, esophageal squamous cell carcinoma, and malignant melanoma (Wozniak et al, 2007;Gao et al, 2013;Hua et al, 2014;Lehnertz et al, 2014;Hu et al, 2019;Dang et al, 2020). Higher G9a expression levels have often been associated with poor prognosis (Chen et al, 2010;Ke et al, 2014;Zhang et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Deficiency of G9a Inhibits Cell Proliferation and Activates Autophagy via Transcriptionally Regulating c-Myc Expression in Glioblastoma

Zhang

Zhong

et al. 2020

Front. Cell Dev. Biol.

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Glioblastoma is an aggressive and difficult to treat cancer. Recent data have emerged implicating that histone modification level may play a crucial role in glioma genesis. The histone lysine methyltransferase G9a is mainly responsible for the mono- and di-methylation of histone H3 lysine 9 (H3K9), whose overexpression is associated with a more aggressive phenotype in cancer. However, the detailed correlations between G9a and glioblastoma genesis remain to be further elucidated. Here, we show that G9a is essential for glioblastoma carcinogenesis and reveal a probable mechanism of it in cell proliferation control. We found that G9a was highly expressed in glioblastoma cells, and knockdown or inhibition of G9a significantly repressed cell proliferation and tumorigenesis ability both in vitro and in vivo. Besides, knockdown or inhibition of G9a led to a cell cycle arrest in G2 phase, as well as decreased the expression of CDK1, CDK2, Cyclin A2, and Cyclin B1, while it induced the activation of autophagy. Further investigation showed that G9a deficiency induced cell proliferation suppression, and activation of autophagy was rescued by overexpression of the full-length c-Myc. Chromatin immunoprecipitation (ChIP) assay showed that G9a was enriched on the −2267 to −1949 region of the c-Myc promoter in LN-229 cells and the −1949 to −1630 region of the c-Myc promoter in U-87 MG cells. Dual-luciferase reporter assay showed that c-Myc promoter activity was significantly reduced after knockdown or inhibition of G9a. Our study shows that G9a controls glioblastoma cell proliferation by transcriptionally modulating oncogene c-Myc and provides insight into the capabilities of G9a working as a potential therapeutic target in glioblastoma.

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G9a and histone deacetylases are crucial for Snail2‐mediated E‐cadherin repression and metastasis in hepatocellular carcinoma

Cited by 40 publications

References 50 publications

Hepigenetics: A Review of Epigenetic Modulators and Potential Therapies in Hepatocellular Carcinoma

Hepigenetics: A Review of Epigenetic Modulators and Potential Therapies in Hepatocellular Carcinoma

Inhibition of histone methyltransferase G9a attenuates liver cancer initiation by sensitizing DNA-damaged hepatocytes to p53-induced apoptosis

Deficiency of G9a Inhibits Cell Proliferation and Activates Autophagy via Transcriptionally Regulating c-Myc Expression in Glioblastoma

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