Abstract
BackgroundA number of JmjC domain-containing histone demethylases have been identified and biochemically characterized in mammalian models and humans. JMJD2A is a transcriptional co-factor and enzyme that catalyzes the demethylation of histone H3 lysine 9 and 36 (H3K9 and H3K36). Here in this study, we reported the role of JMJD2A in human glioma.MethodsQuantitative real-time PCR and western blot were performed to analyzed JMJD2A expression in glioma. Log-rank was performed to plot the survival curve. JMJD2A was knocked or overexpressed with lentivirus. Cell proliferation and colony formation were performed to assess the effects of JMJD2A on glioma cell growth. Xenograft experiment was performed the evaluate the growth rate of glioma cells in vivo. The signaling pathway was analyzed with western blot and mTOR was inhibited with rapamycin.ResultsQuantitative real-time PCR and western blot experiments revealed higher expression of JMJD2A and lower levels of H3K9me3/H3K36me3 in glioma tissues than that in normal brain tissues. We showed that knockdown of JMJD2A expression attenuated the growth and colony formation in three lines of glioma cells (U251, T98G, and U87MG), whereas JMJD2A overexpression resulted in opposing effects. Furthermore, we performed in vivo xenograft experiments and our data demonstrated that JMJD2A knockdown reduced the growth of glioma T98G cells in vivo. Further mechanism study implicated that JMJD2A activated the Akt-mTOR pathway and promoted protein synthesis in glioma cells via promoting phosphoinositide-dependent kinase-1 (PDK1) expression. The activation of the Akt-mTOR pathway was also validated in human glioma tissues. Finally, we showed that inhibition of mTOR with rapamycin blocked the effects of JMJD2A on protein synthesis, cell proliferation and colony formation of glioma cells.ConclusionsThese findings demonstrated that JMJD2A regulated glioma growth and implicated that JMJD2A might be a promising target for intervention.
Highlights
A number of JmjC domain-containing histone demethylases have been identified and biochemically characterized in mammalian models and humans
We found that JmjC Domain-containing 2A (JMJD2A) mRNA was much higher in tissues from glioma than that from normal brain tissues (Fig. 1a)
We provided evidence that the effects of JMJD2A on protein synthesis, cell proliferation, and colony formation were blocked by rapamycin, implicating that mammalian target of rapamycin (mTOR) is essential for JMJD2A function in human glioma cells
Summary
A number of JmjC domain-containing histone demethylases have been identified and biochemically characterized in mammalian models and humans. The JMJD (JmjC domain-containing) proteins, is composed of 30 members in humans based on the presence of the roughly 150 amino acid–long JmjC domain [6]. Among this family, JMJD2A, JMJD2B, and JMJD2C are overexpressed in breast, colorectal, lung, prostate, and other tumors and are required for efficient cancer cell growth [7]. A major of studies focus on JMJD2A has been in transcription regulation, where it may either stimulate or repress gene transcription The latter function of JMJD2A involves association with the nuclear receptor co-repressor complex or histone deacetylases or binding directly to a transcription factor such as the p53 tumor suppressor [8,9,10]. The aim of this study is to determine the role of JMJD2A in human glioma and the underlying mechanism
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