Dataset Information

Upregulation of PSMD10 caused by the JMJD2A histone demethylase.

ABSTRACT: PSMD10, also known as gankyrin, is associated with the proteasome and has been shown to be an oncoprotein in the liver. Here, we report that PSMD10 expression is stimulated by the histone demethylase JMJD2A/KDM4A and its interaction partner, the ETV1 transcription factor, in LNCaP prostate cancer cells. Global analysis of expression patterns revealed that PSMD10 mRNA levels are positively correlated with those of both JMJD2A and ETV1. In human prostate tumors, PSMD10 is highly overexpressed at the protein level and correlates with JMJD2A overexpression; further, PSMD10 expression is enhanced in the prostates of transgenic JMJD2A mice. Moreover, PSMD10 is particularly overexpressed in high Gleason score prostate tumors. Downregulation of PSMD10 in LNCaP prostate cancer cells impaired their growth, indicating that PSMD10 may exert a pro-oncogenic function in the prostate. Lastly, we observed that PSMD10 expression is correlated to YAP1, a component of the Hippo signaling pathway and whose gene promoter is regulated by JMJD2A, and that PSMD10 can cooperate with YAP1 in stimulating LNCaP cell growth. Altogether, these data indicate that PSMD10 is a novel downstream effector of JMJD2A and suggest that inhibition of the JMJD2A histone demethylase by small molecule drugs may be effective to curtail the oncogenic activity of PSMD10 in various PSMD10-overexpressing tumors.

SUBMITTER: Kim TD

PROVIDER: S-EPMC5584593 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Upregulation of PSMD10 caused by the JMJD2A histone demethylase.

Kim Tae-Dong TD Oh Sangphil S Lightfoot Stan A SA Shin Sook S Wren Jonathan D JD Janknecht Ralf R

International journal of clinical and experimental medicine 20160630 6

PSMD10, also known as gankyrin, is associated with the proteasome and has been shown to be an oncoprotein in the liver. Here, we report that PSMD10 expression is stimulated by the histone demethylase JMJD2A/KDM4A and its interaction partner, the ETV1 transcription factor, in LNCaP prostate cancer cells. Global analysis of expression patterns revealed that PSMD10 mRNA levels are positively correlated with those of both JMJD2A and ETV1. In human prostate tumors, PSMD10 is highly overexpressed at t ...[more]

PMID: 28883898

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Project description: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.

Project description:Small ubiquitin-like modifier (SUMO) modification of chromatin has profound effects on transcription regulation. By using Kaposi's sarcoma associated herpesvirus (KSHV) as a model, we recently demonstrated that epigenetic modification of viral chromatin by SUMO-2/3 is involved in regulating gene expression and viral reactivation. However, how this modification orchestrates transcription reprogramming through targeting histone modifying enzymes remains largely unknown. Here we show that JMJD2A, the first identified Jumonji C domain-containing histone demethylase, is the histone demethylase responsible for SUMO-2/3 enrichment on the KSHV genome during viral reactivation. Using in vitro and in vivo SUMOylation assays, we found that JMJD2A is SUMOylated on lysine 471 by KSHV K-bZIP, a viral SUMO-2/3-specific E3 ligase, in a SUMO-interacting motif (SIM)-dependent manner. SUMOylation is required for stabilizing chromatin association and gene transactivation by JMJD2A. These finding suggest that SUMO-2/3 modification plays an essential role in the epigenetic regulatory function of JMJD2A. Consistently, hierarchical clustering analysis of RNA-seq data showed that a SUMO-deficient mutant of JMJD2A was more closely related to JMJD2A knockdown than to wild-type. Our previous report demonstrated that JMJD2A coated and maintained the "ready to activate" status of the viral genome. Consistent with our previous report, a SUMO-deficient mutant of JMJD2A reduced viral gene expression and virion production. Importantly, JMJD2A has been implicated as an oncogene in various cancers by regulating proliferation. We therefore further analyzed the role of SUMO modification of JMJD2A in regulating cell proliferation. Interestingly, the SUMO-deficient mutant of JMJD2A failed to rescue the proliferation defect of JMJD2A knockdown cells. Emerging specific inhibitors of JMJD2A have been generated for evaluation in cancer studies. Our results revealed that SUMO conjugation mediates an epigenetic regulatory function of JMJD2A and suggests that inhibiting JMJD2A SUMOylation may be a novel avenue for anti-cancer therapy.

Dataset Information

Upregulation of PSMD10 caused by the JMJD2A histone demethylase.

Publications

Upregulation of PSMD10 caused by the JMJD2A histone demethylase.

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