Role of JMJD3 Demethylase and Its Inhibitor GSK-J4 in Regulation of MGMT, TRA2A, RPS6KA2, and U2AF1 Genes in Prostate Cancer Cell Lines

Sánchez, Alcides Antúnez; Ouardi, Driss El; Khoufaf, Fatma Zohra Houfaf; Idrissou, Mouhamed; Boisnier, Tiphanie; Penault‐Llorca, Frédérique; Bignon, Yves‐Jean; Guy, Laurent; Bernard‐Gallon, Dominique

doi:10.1089/omi.2020.0054

Cited by 9 publications

(10 citation statements)

References 6 publications

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“…Our results on gene expression after inhibition by GSK-J4 were consistent with those previously performed in vitro on the three cell lines. By contrast, the increase in H3K27me3 gene enrichment after treatment was evident in vitro (36) while disparities have been demonstrated in vivo. It is certain that the tumor microenvironment must be taken into consideration, the tumor stroma, the infiltrating immune cells, and the blood vessels surrounding the tumor lead to molecular events that do not exist in vitro.…”

Section: Discussionmentioning

confidence: 77%

“…These genes are involved in DNA damage repair, mRNA splicing and cell differentiation (34). Furthermore, a link between the androgen receptor (AR), EZH2 (35) and JMJD3 demethylase activity was demonstrated: androgen status resulted in differential accumulation of JMJD3 at candidate genes between AR+ and AR-cells (36) and this was reflected at the transcriptional level (32). JMJD3 is therefore an interesting candidate to study for a better understanding of prostate tumor progression.…”

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confidence: 99%

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Effects of GSK-J4 on JMJD3 Histone Demethylase in Mouse Prostate Cancer Xenografts

Sánchez

Penault‐Llorca

Bignon

et al. 2022

Cancer Genomics Proteomics

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Background/Aim: Histone methylation status is required to control gene expression. H3K27me3 is an epigenetic tri-methylation modification to histone H3 controlled by the demethylase JMJD3. JMJD3 is dysregulated in a wide range of cancers and has been shown to control the expression of a specific growth-modulatory gene signature, making it an interesting candidate to better understand prostate tumor progression in vivo. This study aimed to identify the impact of JMJD3 inhibition by its inhibitor, GSK4, on prostate tumor growth in vivo. Materials and Methods: Prostate cancer cell lines were implanted into Balb/c nude male mice. The effects of the selective JMJD3 inhibitor GSK-J4 on tumor growth were analyzed by bioluminescence assays and H3K27me3-regulated changes in gene expression were analyzed by ChIP-qPCR and RT-qPCR. Results: JMJD3 inhibition contributed to an increase in tumor growth in androgen-independent (AR-) xenografts and a decrease in androgen-dependent (AR+). GSK-J4 treatment modulated H3K27me3 enrichment on the gene panel in DU-145-luc xenografts while it had little effect on PC3-luc and no effect onLNCaP-luc. Effects of JMJD3 inhibition affected the panel gene expression. Conclusion: JMJD3 has a differential effect in prostate tumor progression according to AR status. Our results suggest that JMJD3 is able to play a role independently of its demethylase function in androgenindependent prostate cancer. The effects of GSK-J4 on AR+ prostate xenografts led to a decrease in tumor growth.

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Section: Discussionmentioning

confidence: 77%

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confidence: 99%

Effects of GSK-J4 on JMJD3 Histone Demethylase in Mouse Prostate Cancer Xenografts

Sánchez

Penault‐Llorca

Bignon

et al. 2022

Cancer Genomics Proteomics

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“…Xu et al confirmed that high expression of TRA2A indicates poor prognosis in patients with hepatocellular carcinoma [ 20 ]. Sanchez et al found that TRA2A is a biomarker for the development of prostate cancer [ 21 ]. Liu et al showed that TRA2A promotes taxol resistance and tumor progression in patients with triple-negative breast cancer [ 15 ].…”

Section: Discussionmentioning

confidence: 99%

Transformer 2 alpha homolog is a downstream gene of hypoxia-inducible factor 1 subunit alpha and is involved in the progression of pancreatic cancer

et al. 2022

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Intratumoral hypoxia is a common feature of pancreatic cancer (PC) and also plays a role in its progression. However, hypoxia-regulated signatures in PC are still not completely understood. This study aimed to identify core hypoxia-associated genes and determine their underlying molecular mechanisms in PC cells. Transformer 2 alpha homolog (TRA2A) was found to be an important hypoxia-associated gene, which was upregulated in PC tissues and in PC cells cultured under hypoxia. High TRA2A expression was associated with advanced stage, poor differentiation, and lymph node metastasis. Under normoxic and hypoxic conditions, knockdown of TRA2A both markedly suppressed PC cell proliferation and motility in vitro and in vivo , as well as activation of the AKT pathway. Hypoxia-inducible factor 1 subunit alpha (HIF1α) upregulated the transcription of TRA2A by directly binding to its promoter. TRA2A showed a co-expression relationship with HIF1α in PC tissues. Overexpression of TRA2A alleviated the pro-inhibitive functions of HIF1α-inhibition on PC cell proliferation and motility under hypoxia. In conclusion, TRA2A is a crucial downstream gene of HIF1α that accelerates the proliferation and motility of PC cells. TRA2A may be a novel and practical molecular target for investigating the hypoxic response of PC cells. Abbreviations : TRA2A, transformer 2A protein; PC, pancreatic cancer; HIF1α, hypoxia-inducible factor 1-alpha; GEO, Gene Expression Omnibus; IHC, immunohistochemical staining.

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“…AR is overexpressed in PC, as well as in 30% of castration-resistant PC (CRPC) compared to untreated PC [61]. A number of studies have suggested a possible link between JMJD3, H3K27me3, and the AR metabolic pathway [56,57,[61][62][63][64]]. JMJD3's transcriptional level is increased in LNCaP AR+ tumor cell lines compared to PC-3 AR− tumor cell lines [56].…”

Section: Prostate Cancermentioning

confidence: 99%

“…This comment also applies to JMJD3's enrichment on four candidate genes (O-methylguanine-DNA methyltransferase (MGMT), transformer 2 alpha homolog (TRA2A), 2 small nuclear RNA auxiliary factor 1 (U2AF1), and ribosomal protein S6 kinase A2 (RPS6KA2)), identified as signature genes in PC [59]. After GSK-J4 inhibitory treatment of JMJD3, AR− tumor cells did not show an increase in JMJD3 on the promotor of candidate genes, while AR+ tumor cells did show an increase [62]. This observation was echoed at the transcriptional level on the same genes after inhibitor treatment [56].…”

Section: Prostate Cancermentioning

confidence: 99%

The Functions of the Demethylase JMJD3 in Cancer

Sánchez

Khoufaf

Idrissou

et al. 2021

IJMS

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Cancer is a major cause of death worldwide. Epigenetic changes in response to external (diet, sports activities, etc.) and internal events are increasingly implicated in tumor initiation and progression. In this review, we focused on post-translational changes in histones and, more particularly, the tri methylation of lysine from histone 3 (H3K27me3) mark, a repressive epigenetic mark often under- or overexpressed in a wide range of cancers. Two actors regulate H3K27 methylation: Jumonji Domain-Containing Protein 3 demethylase (JMJD3) and Enhancer of zeste homolog 2 (EZH2) methyltransferase. A number of studies have highlighted the deregulation of these actors, which is why this scientific review will focus on the role of JMJD3 and, consequently, H3K27me3 in cancer development. Data on JMJD3’s involvement in cancer are classified by cancer type: nervous system, prostate, blood, colorectal, breast, lung, liver, ovarian, and gastric cancers.

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Role of JMJD3 Demethylase and Its Inhibitor GSK-J4 in Regulation of MGMT, TRA2A, RPS6KA2, and U2AF1 Genes in Prostate Cancer Cell Lines

Cited by 9 publications

References 6 publications

Effects of GSK-J4 on JMJD3 Histone Demethylase in Mouse Prostate Cancer Xenografts

Effects of GSK-J4 on JMJD3 Histone Demethylase in Mouse Prostate Cancer Xenografts

Transformer 2 alpha homolog is a downstream gene of hypoxia-inducible factor 1 subunit alpha and is involved in the progression of pancreatic cancer

The Functions of the Demethylase JMJD3 in Cancer

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