The pharmacological role of histone demethylase JMJD3 inhibitor GSK-J4 on glioma cells

Sui, Aixia; Xu, Yan; Li, Yitong; Hu, Qilu; Wang, Zeyang; Zhang, Hongtao; Yang, Junjie; Guo, Xiaoqiang; Zhao, Wenqing

doi:10.18632/oncotarget.19793

Cited by 43 publications

(42 citation statements)

References 29 publications

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“…JMJD2A depletion reduced the expression of SNAI1 , CDH2 , VIM and PAI induced by TGF-β1 ( Supplementary Figure S6E and F ), but did not change TGF-β1-mediated repression of WIF1 , MYC , CDH1 and DSP ( Supplementary Figures S6G and H, and S6-Stat.1–7 ). The same phenotype was observed by inhibiting JMJD2 activity with JIB04 ( 50 , 51 ) ( Supplementary Figures S3 and S6-Stat.1–7 ). We conclude that JMJD2A cooperates with LSD1 to activate TGF-β1-induced EMT genes and it is not required for TGF-β1 silencing of epithelial genes.…”

Section: Resultssupporting

confidence: 68%

Targeted DNA oxidation by LSD1–SMAD2/3 primes TGF-β1/ EMT genes for activation or repression

Pezone

Taddei

Tramontano

et al. 2020

Nucleic Acids Research

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The epithelial-to-mesenchymal transition (EMT) is a complex transcriptional program induced by transforming growth factor β1 (TGF-β1). Histone lysine-specific demethylase 1 (LSD1) has been recognized as a key mediator of EMT in cancer cells, but the precise mechanism that underlies the activation and repression of EMT genes still remains elusive. Here, we characterized the early events induced by TGF-β1 during EMT initiation and establishment. TGF-β1 triggered, 30–90 min post-treatment, a nuclear oxidative wave throughout the genome, documented by confocal microscopy and mass spectrometry, mediated by LSD1. LSD1 was recruited with phosphorylated SMAD2/3 to the promoters of prototypic genes activated and repressed by TGF-β1. After 90 min, phospho-SMAD2/3 downregulation reduced the complex and LSD1 was then recruited with the newly synthesized SNAI1 and repressors, NCoR1 and HDAC3, to the promoters of TGF-β1-repressed genes such as the Wnt soluble inhibitor factor 1 gene (WIF1), a change that induced a late oxidative burst. However, TGF-β1 early (90 min) repression of transcription also required synchronous signaling by reactive oxygen species and the stress-activated kinase c-Jun N-terminal kinase. These data elucidate the early events elicited by TGF-β1 and the priming role of DNA oxidation that marks TGF-β1-induced and -repressed genes involved in the EMT.

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Section: Resultssupporting

confidence: 68%

Targeted DNA oxidation by LSD1–SMAD2/3 primes TGF-β1/ EMT genes for activation or repression

Pezone

Taddei

Tramontano

et al. 2020

Nucleic Acids Research

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“…In the present study, we employed the human leukemia U937 cell line as a well-established and widely used model system of human leukemic cells ( Shayo et al, 2004 ; Copsel et al, 2011 ). Throughout our in vitro experiments, we used 10 μM final concentration of forskolin (not toxic, submaximal dose), in agreement with several studies regarding in vitro effects by forskolin, ranging from 1 up to 100 μM ( Shayo et al, 2004 ; Dong et al, 2015 ; Follin-Arbelet et al, 2015 ; Park and Juhnn, 2016 ; Pattabiraman et al, 2016 ; Xiao and Kan, 2017 ), and a spectrum of final concentration of GSKJ4 up to 10 μM, according to previous findings ( Hashizume et al, 2014 ; Ntziachristos et al, 2014 ; Sakaki et al, 2015 ; Watarai et al, 2016 ; Dalvi et al, 2017 ; Mathur et al, 2017 ; Sui et al, 2017 ; Yan et al, 2017 ; Rejlova et al, 2018 ).…”

Section: Resultsmentioning

confidence: 96%

“…Recently, GSKJ4 has been shown to inhibit the proliferation of many types of cancer cells at micromolar concentrations, with low/no toxicity to normal cells ( Hashizume et al, 2014 ; Ntziachristos et al, 2014 ; Sakaki et al, 2015 ; Watarai et al, 2016 ; Dalvi et al, 2017 ; Mathur et al, 2017 ; Sui et al, 2017 ; Yan et al, 2017 ). Firstly, we investigated whether GSKJ4 could have an antiproliferative action also on U937 cells and whether forskolin could affect such possible action.…”

Section: Resultsmentioning

confidence: 99%

“…GSKJ4 is a novel, selective inhibitor of the jumonji family of histone demethylases JMJD3 and UTX, which are the H3K27me2/3-specific demethylases, catalyzing the demethylation of H3K27me2/3. To note, GSKJ4 has been recently shown to act as a potent small molecule inhibitor of the proliferation of cancer cells, including glioma, breast, ovarian, lung cancer cells ( Hashizume et al, 2014 ; Sakaki et al, 2015 ; Watarai et al, 2016 ; Dalvi et al, 2017 ; Sui et al, 2017 ; Yan et al, 2017 ). Additionally, in diffuse large B-cell lymphoma GSKJ4 is directly toxic as a single agent and also sensitizes the cells to various clinically approved drugs ( Mathur et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

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Forskolin Sensitizes Human Acute Myeloid Leukemia Cells to H3K27me2/3 Demethylases GSKJ4 Inhibitor via Protein Kinase A

et al. 2018

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Acute myeloid leukemia (AML) is an aggressive hematological malignancy occurring very often in older adults, with poor prognosis depending on both rapid disease progression and drug resistance occurrence. Therefore, new therapeutic approaches are demanded. Epigenetic marks play a relevant role in AML. GSKJ4 is a novel inhibitor of the histone demethylases JMJD3 and UTX. To note GSKJ4 has been recently shown to act as a potent small molecule inhibitor of the proliferation in many cancer cell types. On the other hand, forskolin, a natural cAMP raising compound, used for a long time in traditional medicine and considered safe also in recent studies, is emerging as a very interesting molecule for possible use in cancer therapy. Here, we investigate the effects of forskolin on the sensitivity of human leukemia U937 cells to GSKJ4 through flow cytometry-based assays (cell-cycle progression and cell death), cell number counting, and immunoblotting experiments. We provide evidence that forskolin markedly potentiates GSKJ4-induced antiproliferative effects by apoptotic cell death induction, accompanied by a dramatic BCL2 protein down-regulation as well as caspase 3 activation and PARP protein cleavage. Comparable effects are observed with the phosphodiesterase inhibitor IBMX and 8-Br-cAMP analogous, but not by using 8-pCPT-2′-O-Me-cAMP Epac activator. Moreover, the forskolin-induced enhancement of sensitivity to GSKJ4 is counteracted by pre-treatment with Protein Kinase A (PKA) inhibitors. Altogether, our data strongly suggest that forskolin sensitizes U937 cells to GSKJ4 inhibitor via a cAMP/PKA-mediated mechanism. Our findings provide initial evidence of anticancer activity induced by forskolin/GSKJ4 combination in leukemia cells and underline the potential for use of forskolin and GSKJ4 in the development of innovative and effective therapeutic approaches for AML treatment.

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“…Mutations of H3.3- H3FA are uncommon in adult GBM where H3.3 can be functionally inactivated by the MLL5 gene that is overexpressed in GBM stem cultures ( 80 ). Finally, it was found that GSK J4, like in pediatric GBM, has strong suppressive effects on cell viability and self-renewal properties ( 80 , 81 ).…”

Section: Targeting Epigenetic Alterations In Glioblastomamentioning

confidence: 99%

Epigenetic Targeting of Glioblastoma

2018

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Glioblastoma is one of the first tumors where the biological changes accompanying a single epigenetic modification, the methylation of the MGMT gene, were found to be of clinical relevance. The exploration of the epigenomic landscape of glioblastoma has allowed to identify patients carrying a diffuse hypermethylation at gene promoters and with better outcome. Epigenetic and genetic data have led to the definition of major subgroups of glioma and were the basis of the current WHO classification of CNS tumors and of a novel classification based solely on DNA methylation data that shows a remarkable diagnostic precision.The reversibility of epigenetic modifications is considered a therapeutic opportunity in many tumors also because these alterations have been mechanistically linked to the biological characteristics of glioblastoma. Several alterations like IDH1/2 mutations that interfere with “epigenetic modifier” enzymes, the mutations of the histone 3 variants H3.1 and H3.3 that alter the global H3K27me3 levels and the altered expression of histone methyltransferases and demethylases are considered potentially druggable targets in glioma and molecules targeting these alterations are being tested in preclinical and clinical trials. The recent advances on the knowledge of the players of the “epigenetic orchestra” and of their mutual interactions are indicating new paths that may eventually open new therapeutic options for this invariably lethal cancer.

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The pharmacological role of histone demethylase JMJD3 inhibitor GSK-J4 on glioma cells

Cited by 43 publications

References 29 publications

Targeted DNA oxidation by LSD1–SMAD2/3 primes TGF-β1/ EMT genes for activation or repression

Targeted DNA oxidation by LSD1–SMAD2/3 primes TGF-β1/ EMT genes for activation or repression

Forskolin Sensitizes Human Acute Myeloid Leukemia Cells to H3K27me2/3 Demethylases GSKJ4 Inhibitor via Protein Kinase A

Epigenetic Targeting of Glioblastoma

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