Histone Methyltransferase G9a Drives Chemotherapy Resistance by Regulating the Glutamate–Cysteine Ligase Catalytic Subunit in Head and Neck Squamous Cell Carcinoma

Liu, Chia-Wen; Hua, Kuo Tai; Li, Kaichun; Kao, Hsiang‐Fong; Hong, Ruey‐Long; Ko, Jenq‐Yuh; Hsiao, Michael; Kuo, Min-Liang; Tan, Ching-Ting

doi:10.1158/1535-7163.mct-16-0567-t

Cited by 45 publications

(28 citation statements)

References 46 publications

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“…Several reports have indicated that EHMT2 expression and enzymatic activity were associated with malignant behaviors, such as tumor growth, cell invasion, cancer stem cell phenotypes and survival, in various cancer types 23 – 25 . Liu et al 26 recently found that EHMT2 protected head and neck squamous cell carcinoma cells against cisplatin by increasing GSH expression, suggesting that EHMT2 is a promising target for the prevention of chemotherapy resistance in patients undergoing cancer treatment. Our results also demonstrated that EHMT2 expression and enzymatic activity levels were upregulated in NSCLC EGFR-TKI-resistant cells.…”

Section: Discussionmentioning

confidence: 99%

Targeting EHMT2 reverses EGFR-TKI resistance in NSCLC by epigenetically regulating the PTEN/AKT signaling pathway

et al. 2018

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Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance is a major obstacle in the treatment of non-small cell lung cancer (NSCLC). Epigenetic alterations have been shown to be involved in NSCLC oncogenesis; however, their function in EGFR-TKI resistance remains uncharacterized. Here, we found that an EHMT2 inhibitor, UNC0638, can significantly inhibit cell growth and induce apoptosis in EGFR-TKI-resistant NSCLC cells. Additionally, we also found that EHMT2 expression and enzymatic activity levels were elevated in EGFR-TKI-resistant NSCLC cells. Moreover, we determined that genetic or pharmacological inhibition of EHMT2 expression enhanced TKI sensitivity and suppressed migration and tumor sphere formation in EGFR-TKI-resistant NSCLC cells. Further investigation revealed that EHMT2 contributed to PTEN transcriptional repression and thus facilitated AKT pathway activation. The negative relationship between EHMT2 and PTEN was confirmed by our clinical study. Furthermore, we determined that combination treatment with the EHMT2 inhibitor and Erlotinib resulted in enhanced antitumor effects in a preclinical EGFR-TKI-resistance model. We also found that high EHMT2 expression along with low PTEN expression can predict poor overall survival in patients with NSCLC. In summary, our findings showed that EHMT2 facilitated EGFR-TKI resistance by regulating the PTEN/AKT pathway in NSCLC cells, suggesting that EHMT2 may be a target in the clinical treatment of EGFR-TKI-resistant NSCLC.

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Section: Discussionmentioning

confidence: 99%

Targeting EHMT2 reverses EGFR-TKI resistance in NSCLC by epigenetically regulating the PTEN/AKT signaling pathway

et al. 2018

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“…GCL is composed of a large catalytic subunit (GCLC) and a small modified subunit ( 5 , 8 ). GCLC was recently reported to be involved in tamoxifen resistance in breast cancer ( 9 ) and cisplatin resistance in head and neck squamous cell carcinoma ( 10 ). Cysteine is mainly supplied from outside of the cell as a form of cystine via a cystine-glutamate transporter, xc(-), which was previously reported to be related to cancer chemoresistance ( 11 , 12 ).…”

Section: Introductionmentioning

confidence: 99%

Glutamate-cysteine ligase catalytic subunit is associated with cisplatin resistance in lung adenocarcinoma

Hiyama

Ando

Maemura

et al. 2018

Japanese Journal of Clinical Oncology

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“…In addition, G9a expression is closely associated with tumorigenesis, metastasis and drug resistance in many cancers [36]. We previously reported that G9a promotes tumor growth via enhancing HP1α and silencing APC2 expression (19).Researchers have shown that G9ais transcriptionally regulated by special AT-rich sequence-binding protein 2 (SATB2).…”

Section: Discussionmentioning

confidence: 99%

Histone Methyltransferase G9a Promotes Invasion of Non-small Cell Lung Cancer Through Enhancing Focaladhesionkinase Activationvia NF-KB Signaling Pathway

Sun¹,

Zhang²,

Pangeni³

et al. 2020

Preprint

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BackgroundOverexpression of euchromatic histone methyltransferase 2 (EHMT2 or G9a) is frequently found in a number of human cancers. Potential roles of G9a in invasion and metastasis are not well understood in non-small cell lung cancer (NSCLC). Here we investigated the effect and underlying mechanisms of G9a, and therapeutic implications of targeting G9a in the invasion of NSCLC. MethodsG9a-associated gene sets were identified by RNAseq analysis. Migration and invasion assays were applied to examine the impact of targeting G9a by siRNA knockdown orits specific inhibitor UNC0638 in NSCLC cells. Rescue experiments were designed to investigate the effect of focal adhesion kinase (FAK) and NF-κB inhibitors on the invasion of NSCLC cells overexpressing G9a. Correlation between the protein level of phosphorylated FAK and G9a was analyzed in NSCLC tissues.ResultsKnockdown and inhibition of G9a drastically suppressed in vitro cellular proliferation, migration, and invasion; while overexpression of G9a significantly enhanced proliferation, migration, and invasion of A549 and H1299 NSCLC cells. Targeting G9a led to a significant decrease in the expression of FAK protein and activation of FAK signaling pathway in both A549 and H1299 cells. Additionally, defactinib, a potent FAK inhibitor, partially abolished the enhanced migration and invasion by overexpression of G9a in these NSCLC cells. Furthermore, G9a was found to boost nuclear factor-kappa B (NF-κB) transcriptional activity in NSCLC cells through partially downregulating inhibitor of κB (IκBα), and an NF-κB inhibitor partially abolished the enhanced FAK activation by overexpressed G9a, which suggests that G9a-enhanced invasion and activation of FAK may be mediated by elevated NF-κB activity. Notably, a strong positive correlation between the immunohistochemical staining of G9a and phosphorylated FAK proteins was identified in H1299 xenografts and 159 cases of NSCLC tissues (R = 0.408).ConclusionsThese data strongly demonstrate that G9a may promote invasion and metastasis of NSCLC cells by enhancing FAK signaling pathway via elevating NF-κB transcriptional activity, indicating potential significance and therapeutic implications of these pathways in the invasion and metastasis of NSCLCs that overexpress G9a protein.

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Histone Methyltransferase G9a Drives Chemotherapy Resistance by Regulating the Glutamate–Cysteine Ligase Catalytic Subunit in Head and Neck Squamous Cell Carcinoma

Cited by 45 publications

References 46 publications

Targeting EHMT2 reverses EGFR-TKI resistance in NSCLC by epigenetically regulating the PTEN/AKT signaling pathway

Targeting EHMT2 reverses EGFR-TKI resistance in NSCLC by epigenetically regulating the PTEN/AKT signaling pathway

Glutamate-cysteine ligase catalytic subunit is associated with cisplatin resistance in lung adenocarcinoma

Histone Methyltransferase G9a Promotes Invasion of Non-small Cell Lung Cancer Through Enhancing Focaladhesionkinase Activationvia NF-KB Signaling Pathway

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