Abstract

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.

Highlights

  • Glioblastoma is one of the most aggressive and deadliest cancers with a uniformly poor patient prognosis (Silantyev et al, 2019)

  • The expression of G9a in glioblastoma cells was decreased after inhibitor treatment (Figure 1I) and G9a-shRNA-induced gene knockdown, and the no.1 shG9a had the higher effectivity in knockdown G9a expression (Figure 1B)

  • We found that the expression of CDK1, CDK2, Cyclin A2, and Cyclin B1 was declined in both inhibitor-treatment cells and G9a-knockdown cells (Figures 1F,K)

Read more

Summary

Introduction

Glioblastoma is one of the most aggressive and deadliest cancers with a uniformly poor patient prognosis (Silantyev et al, 2019). Traditional anti-cancer treatment is inefficient against glioblastoma due to its high proliferation ability and its extremely strong invasion capacity. Recent data have emerged, implicating that histone modification level may play a crucial role in glioma genesis. Besides its ability to methylate substrates, G9a has been considered as a gene to have methyltransferase-independent activities that influence the expression of target gene (Lee et al, 2006; Purcell et al, 2011; Bittencourt et al, 2012). G9a may act as an important regulator in glioblastoma with its methyltransferase activity or methyltransferase-independent function

Methods
Results
Discussion
Conclusion
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call