Inhibition of H3K9 Methyltransferase G9a Repressed Cell Proliferation and Induced Autophagy in Neuroblastoma Cells

Abstract

Histone methylation plays an important role in gene transcription and chromatin organization and is linked to the silencing of a number of critical tumor suppressor genes in tumorigenesis. G9a is a histone methyltransferase (HMTase) for histone H3 lysine 9. In this study, we investigated the role of G9a in neuroblastoma tumor growth together with the G9a inhibitor BIX01294. The exposure of neuroblastoma cells to BIX01294 resulted in the inhibition of cell growth and proliferation, and BIX01294 treatment resulted in the inhibition of the tumorigenicity of neuroblastoma cells in NOD/SCID mice. Therefore, G9a may be a potential therapeutic target in neuroblastoma. Moreover, we found several specific characteristics of autophagy after BIX01294 treatment, including the appearance of membranous vacuoles and microtubule-associated protein light chain 3 (LC3B). Similar results were observed in G9a-knockdown cells. In conclusion, our results demonstrated that G9a is a prognostic marker in neuroblastoma, and revealed a potential role of G9a in regulating the autophagy signaling pathway in neuroblastoma.

Inhibition of EHMT2/G9a epigenetically increases the transcription ofBeclin-1via an increase in ROS and activation of NF-κB

“…Moreover, EHMT2 suppression induces autophagy and represses cell proliferation in neuroblastoma [44, 45] or peritoneal metastasis in ovarian cancer [46]. Although elevated levels of EHMT2 expression have previously been observed in various cancer tissues when compared with normal tissues, the clinical significance of EHMT2 expression in tumors not yet been fully elucidated.…”

Synthesis and biological evaluation of benzimidazole derivatives as the G9a Histone Methyltransferase inhibitors that induce autophagy and apoptosis of breast cancer cells

“…We analyzed the mitochondrial membrane potential by flow cytometry and found the signally decrease of mitochondrial membrane potential in GA001 treated MCF7 cells ( Figure 6C). Given that G9a is closely associated with cell cycle and DNA damage in different cells [25,28,29], we checked the expression of key cell cycle proteins CDK2 and Cyclin E. We found that GA001 obviously downregulated the expressions of CDK2 and Cyclin E ( Figure 6D). Since the pro-apoptosis protein Bim is negatively regulated by CDK2…”

BIX01294, an inhibitor of histone methyltransferase, induces autophagy-dependent differentiation of glioma stem-like cells

“…BIX01294, a specific inhibitor of G9a29, induced autophagy or autophagy-associated cell death in several tumor cell lines3031323334, but underlying mechanisms have not been explored in glioma cells. Treatment with BIX01294 reduced methylation of H3K9 and H3K27, and at higher concentrations impaired viability of rat C6 glioma cells35.…”