The Functions of the Demethylase JMJD3 in Cancer

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

doi:10.3390/ijms22020968

Cited by 17 publications

(13 citation statements)

References 113 publications

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“…In this study, we demonstrated that JMJD3 and H3K27me3 have a role in prostate cancer progression.H3K27me3, whose demethylation is regulated by JMJD3, was found to be underor over-expressed in a wide range of cancers (29). This study aims to identify the impact of JMJD3 inhibition by its inhibitor, GSK4, on prostate tumor growth in vivo.…”

Section: Discussionmentioning

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: 99%

“…JMJD3 is often over or under expressed in a large variety of cancers including, but no limited to nervous system, prostate, blood, colorectal, breast, lung, liver, ovarian, gastric cancers. This makes the demethylase difficult to classify as a tumor suppressor or oncoprotein (29).…”

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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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“…Combined with the existing literature, we speculate that this may be related to the methylation of H3K27me3 at the promoter of this gene; PTEN has been demonstrated to promote the expression of CTNNA1 and thus inhibit myeloproliferation. The role of other pathways, such as JMJD3 and HOX [48], associated with CTNNA1 still needs to be further validated (Fig. 3A).…”

Section: Role Of Ctnna1 In Hematologic Malignanciesmentioning

confidence: 99%

The Role of CTNNA1 in Malignancies: An Updated Review

Huang¹,

Xu²,

Li³

et al. 2023

J. Cancer

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Catenin alpha 1 (CTNNA1), encoding α-catenin, is involved in several physiological activities, such as adherens junction synthesis and signal transduction. Recent studies have suggested additional functions for CTNNA1 malignancies. This review systematically summarizes the varying functions of CTNNA1 in different tumors and briefly describes the diverse pathways and mechanisms involved in different types of tumors. CTNNA1 is abnormally expressed in leukemia and solid tumor such as cancers of digestive system, genitourinary system and breast, and it's related to the occurrence, development, and prognosis of tumors. In addition, the possible physiological processes involving CTNNA1, such as methylation, miRNA interference, or regulatory axes, similar to those of CDH1, SETD2, and hsa-miR-30d-5p/GJA1 are also summarized here. The precise mechanism of CTNNA1 in most cancers remains uncertain; hence, additional pre-clinical studies of CTNNA1 are warranted for potential early tumor diagnosis, prognosis, and treatment.

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“…80 The genomic instability that emerges and propagates during the expansion of malignant clonal prostate cancer cells likely creates a fertile environment for genetic disruption of these chromatin regulators. These chromatin regulatory enzymes are being considered as therapeutic targets for small molecule inhibition in several cancers, 81 including prostate cancer. 82,83 Thus, small molecule inhibitors targeting individual BET bromodomain proteins, in combination with inhibitors of other chromatin regulators, represent an innovative approach to solve the problem of emerging ADT-resistant forms of prostate cancer.…”

Section: Chromatin Regulators In Mechanisms Of Emt and Chemoresistancementioning

confidence: 99%

Novel forms of prostate cancer chemoresistance to successful androgen deprivation therapy demand new approaches: Rationale for targeting BET proteins

et al. 2022

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In patients with prostate cancer, the duration of remission after treatment with androgen deprivation therapies (ADTs) varies dramatically. Clinical experience has demonstrated difficulties in predicting individual risk for progression due to chemoresistance. Drug combinations that inhibit androgen biosynthesis (e.g., abiraterone acetate) and androgen signaling (e.g., enzalutamide or apalutamide) have proven so effective that new forms of ADT resistance are emerging. In particular, prostate cancers with a neuroendocrine transcriptional signature, which demonstrate greater plasticity, and potentially, increased predisposition to metastasize, are becoming more prevalent. Notably, these subtypes had in fact been relatively rare before the widespread success of novel ADT regimens.Therefore, better understanding of these resistance mechanisms and potential alternative treatments are necessary to improve progression-free survival for patients treated with ADT. Targeting the bromodomain and extra-terminal (BET) protein family, specifically BRD4, with newer investigational agents may represent one such option.Several families of chromatin modifiers appear to be involved in ADT resistance and targeting these pathways could also offer novel approaches. However, the limited transcriptional and genomic information on ADT resistance mechanisms, and a serious lack of patient diversity in clinical trials, demand profiling of a much broader clinical and demographic range of patients, before robust conclusions can be drawn and a clear direction established.

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The Functions of the Demethylase JMJD3 in Cancer

Cited by 17 publications

References 113 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

The Role of CTNNA1 in Malignancies: An Updated Review

Novel forms of prostate cancer chemoresistance to successful androgen deprivation therapy demand new approaches: Rationale for targeting BET proteins

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