<scp>JARID</scp>1B expression and its function in <scp>DNA</scp> damage repair are tightly regulated by mi<scp>RNA</scp>s in breast cancer

Mocavini, Ivano; Pippa, Simone; Licursi, Valerio; Paci, Paola; Trisciuoglio, Daniela; Mannironi, Cecilia; Presutti, Carlo; Negri, Rodolfo

doi:10.1111/cas.13925

Cited by 26 publications

(29 citation statements)

References 48 publications

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“…We recently found two microRNAs which specifically target and repress KDM5B which are strongly down-regulated in breast tumors [55]. These miRNAs can decrease KDM5B protein expression in different breast cancer cell lines, including MCF-7 and at the same time increase their radio-sensitivity [55].…”

Section: Discussionmentioning

confidence: 99%

Small Molecule Inhibitors of KDM5 Histone Demethylases Increase the Radiosensitivity of Breast Cancer Cells Overexpressing JARID1B

et al. 2019

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Background: KDM5 enzymes are H3K4 specific histone demethylases involved in transcriptional regulation and DNA repair. These proteins are overexpressed in different kinds of cancer, including breast, prostate and bladder carcinomas, with positive effects on cancer proliferation and chemoresistance. For these reasons, these enzymes are potential therapeutic targets. Methods: In the present study, we analyzed the effects of three different inhibitors of KDM5 enzymes in MCF-7 breast cancer cells over-expressing one of them, namely KDM5B/JARID1B. In particular we tested H3K4 demethylation (western blot); radio-sensitivity (cytoxicity and clonogenic assays) and damage accumulation (COMET assay and kinetics of H2AX phosphorylation). Results: we show that all three compounds with completely different chemical structures can selectively inhibit KDM5 enzymes and are capable of increasing sensitivity of breast cancer cells to ionizing radiation and radiation-induced damage. Conclusions: These findings confirm the involvement of H3K4 specific demethylases in the response to DNA damage, show a requirement of the catalytic function and suggest new strategies for the therapeutic use of their inhibitors.

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Section: Discussionmentioning

confidence: 99%

Small Molecule Inhibitors of KDM5 Histone Demethylases Increase the Radiosensitivity of Breast Cancer Cells Overexpressing JARID1B

et al. 2019

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“…There is also evidence that KDM5B regulates H3K4me levels near DSBs sites to facilitate the access of DNA repair enzymes, and its attenuation or pharmacological inhibition increased radioresistance in cancer cells (Bayo et al, 2018). The regulation of KDM5B in the context of GDR seems to be controlled by miRNAs (Mocavini et al, 2019). Not only KDMs but also histone methyltransferases (KMTs) of H3K4 (e.g., SET-2/SET1), appear to be required for protecting genome integrity during meiosis (Sommermeyer et al, 2013;Herbette et al, 2017;Adam et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Histone Lysine Demethylases KDM5B and KDM5C Modulate Genome Activation and Stability in Porcine Embryos

Glanzner

Gutierrez

Rissi

et al. 2020

Front. Cell Dev. Biol.

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The lysine demethylases KDM5B and KDM5C are highly, but transiently, expressed in porcine embryos around the genome activation stage. Attenuation of KDM5B and KDM5C mRNA hampered embryo development to the blastocyst stage in fertilized, parthenogenetically activated and nuclear transfer embryos. While KDM5B attenuation increased H3K4me2-3 levels on D3 embryos and H3K4me1-2-3 on D5 embryos, KDM5C attenuation increased H3K9me1 on D3 embryos, and H3K9me1 and H3K4me1 on D5 embryos. The relative mRNA abundance of EIF1AX and EIF2A on D3 embryos, and the proportion of D4 embryos presenting a fluorescent signal for uridine incorporation were severely reduced in both KDM5B-and KDM5Cattenuated compared to control embryos, which indicate a delay in the initiation of the embryo transcriptional activity. Moreover, KDM5B and KDM5C attenuation affected DNA damage response and increased DNA double-strand breaks (DSBs), and decreased development of UV-irradiated embryos. Findings from this study revealed that both KDM5B and KDM5C are important regulators of early development in porcine embryos as their attenuation altered H3K4 and H3K9 methylation patterns, perturbed embryo genome activation, and decreased DNA damage repair capacity.

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“…KDM5B is upregulated in several tumors and cancer-derived cell lines, which seems to be associated with resistance to genotoxic stress ( Xu et al, 2018 ). Moreover, microRNAs that specifically target KDM5 mRNA are downregulated in tumors and, when overexpressed in cancer cells, increase their radio-sensitivity ( Mocavini et al, 2019 ). KDM5B associates with several other proteins with transcription repressing activities, such as the HDM LSD1, the histone deacetylase HDAC1 and the histone methylase EZH2 ( Figure 1 ).…”

Section: Lysine Methylation In Histone H3 Tailmentioning

confidence: 99%

The Role of Histone Lysine Methylation in the Response of Mammalian Cells to Ionizing Radiation

et al. 2021

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Eukaryotic genomes are wrapped around nucleosomes and organized into different levels of chromatin structure. Chromatin organization has a crucial role in regulating all cellular processes involving DNA-protein interactions, such as DNA transcription, replication, recombination and repair. Histone post-translational modifications (HPTMs) have a prominent role in chromatin regulation, acting as a sophisticated molecular code, which is interpreted by HPTM-specific effectors. Here, we review the role of histone lysine methylation changes in regulating the response to radiation-induced genotoxic damage in mammalian cells. We also discuss the role of histone methyltransferases (HMTs) and histone demethylases (HDMs) and the effects of the modulation of their expression and/or the pharmacological inhibition of their activity on the radio-sensitivity of different cell lines. Finally, we provide a bioinformatic analysis of published datasets showing how the mRNA levels of known HMTs and HDMs are modulated in different cell lines by exposure to different irradiation conditions.

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JARID1B expression and its function in DNA damage repair are tightly regulated by miRNAs in breast cancer

Cited by 26 publications

References 48 publications

Small Molecule Inhibitors of KDM5 Histone Demethylases Increase the Radiosensitivity of Breast Cancer Cells Overexpressing JARID1B

Small Molecule Inhibitors of KDM5 Histone Demethylases Increase the Radiosensitivity of Breast Cancer Cells Overexpressing JARID1B

Histone Lysine Demethylases KDM5B and KDM5C Modulate Genome Activation and Stability in Porcine Embryos

The Role of Histone Lysine Methylation in the Response of Mammalian Cells to Ionizing Radiation

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