Depletion of Histone Demethylase Jarid1A Resulting in Histone Hyperacetylation and Radiation Sensitivity Does Not Affect DNA Double-Strand Break Repair

Penterling, Corina; Drexler, G.; Böhland, Claudia; Stamp, Ramona; Wilke, Christina; Braselmann, Herbert; Caldwell, Randolph B.; Reindl, Judith; Girst, Stefanie; Greubel, C.; Siebenwirth, Christian; Mansour, Waël; Borgmann, Kerstin; Dollinger, G.; Unger, Kristian; Friedl, Anna A.

doi:10.1371/journal.pone.0156599

Cited by 15 publications

(17 citation statements)

References 95 publications

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“…The authors proposed that this is probably because demethylating activity at the sites of damage is mostly carried out by JARID1B, as observed in Li et al (2014) . Instead, sensitivity to ionizing radiation observed upon JARID1A depletion might be due to concurrent histone hyperacetylation …”

Section: Introductionmentioning

confidence: 94%

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

et al. 2019

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JARID 1B/ KDM 5B histone demethylase's mRNA is markedly overexpressed in breast cancer tissues and cell lines and the protein has been shown to have a prominent role in cancer cell proliferation and DNA repair. However, the mechanism of its post‐transcriptional regulation in cancer cells remains elusive. We performed a computational analysis of transcriptomic data from a set of 103 breast cancer patients, which, along with JARID 1B upregulation, showed a strong downregulation of 2 microRNAs (mi RNAs ), mir‐381 and mir‐486, potentially targeting its mRNA . We showed that both mi RNA s can target JARID 1B 3′ UTR and reduce luciferase's activity in a complementarity‐driven repression assay. Moreover, MCF 7 breast cancer cells overexpressing JARID 1B showed a strong protein reduction when transfected with mir‐486. This protein's decrease is accompanied by accumulation of DNA damage, enhanced radiosensitivity and increase of BRCA 1 mRNA , 3 features previously correlated with JARID 1B silencing. These results enlighten an important role of a mi RNA’ s circuit in regulating JARID 1B's activity and suggest new perspectives for epigenetic therapies.

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Section: Introductionmentioning

confidence: 94%

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

et al. 2019

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“…This state was mediated by JARID1A but surprisingly could be depleted by HDAC inhibition. Cooperative HDAC/JARID1 interactions are further evidenced by JARID1A depletion causing a global increase of histone acetylation along with radiosensitization [66]. Insight into such effects was provided by HDAC inhibition increasing global H3K4me3 while suppressing JARID1 demethylase transcription by downregulating Sp1 [123].…”

Section: Jarid1-mediated Transcriptional Regulationmentioning

confidence: 99%

“…JARID1 proteins were first linked to DNA damage when JARID1A was shown to accumulate at γ-H2AX foci and decrease H3K4me3 at those sites after irradiation [65]. However, an increase in radiation sensitivity seen after JARID1A depletion in HeLa cells did not result from deficient double-stranded break repair [66]. JARID1B was implicated in repair of double strand breaks after its loss was shown to promote spontaneous DNA damage and sensitize both osteosarcoma and breast cancer cell lines to genotoxic insult.…”

Section: Jarid1 Contribution To Cancer Progressionmentioning

confidence: 99%

JARID1 Histone Demethylases: Emerging Targets in Cancer

et al. 2017

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JARID1 proteins are histone demethylases that both regulate normal cell fates during development and contribute to the epigenetic plasticity that underlies malignant transformation. This H3K4 demethylase family participates in multiple repressive transcriptional complexes at promoters and has broader regulatory effects on chromatin that remain ill-defined. There is growing understanding of the oncogenic and tumor suppressive functions of JARID1 proteins, which are contingent on cell context and the protein isoform. Their contributions to stem cell-like de-differentiation, tumor aggressiveness, and therapy resistance in cancer have sustained interest in the development of JARID1 inhibitors. Here we review the diverse and context-specific functions of the JARID1 proteins that may impact the utilization of emerging targeted inhibitors of this histone demethylase family in cancer therapy.

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“…The γ‐H2AX complex is a well‐known marker of DNA damage which can also be used as an index for cell radiosensitivity . A positive correlation existed between γ‐HA2X expression and unpaired, damaged DNA . Indeed, in our in vivo analyses it appears that the combination of Icotinib with radiation therapy significantly upregulated γ‐H2AX expression compared with each individual therapy, indicating that Icotinib slows down the cancer cell's ability to repair radiation‐induced DNA damage.…”

Section: Discussionmentioning

confidence: 69%

Icotinib enhances lung cancer cell radiosensitivity in vitro and in vivo by inhibiting MAPK/ERK and AKT activation

Zhang

Wang

2018

Clin Exp Pharma Physio

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Icotinib hydrochloride is a small epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) that was developed by Chinese scientists. While clinical trials have revealed its efficacy in the treatment of lung cancer, very little is known about its role in enhancing radiosensitivity. In this study, we investigated the effectiveness of Icotinib in enhancing lung cancer cell radiosensitivity and have detailed its underlying molecular mechanism. The lung cancer cell line H1650 was pretreated with or without Icotinib for 24 hours before radiation, and clonogenic survival assay was performed. Cell apoptosis was also analyzed by flow cytometry, while western blotting was performed to examine the activation of EGFR and its downstream kinases in H1650 cells after Icotinib and radiation treatment. Furthermore, a xenograft animal model was established to evaluate the radiosensitivity of Icotinib in vivo and to confirm its mechanism. Our results demonstrate that pretreatment with Icotinib reduced clonogenic survival after radiation, inhibited EGFR activation, and increased radiation-induced apoptosis in H1650 cells. The phosphorylation of protein kinase B (AKT), extracellular regulated protein kinase 1/2 (ERK1/2), and EGFR was inhibited after Icotinib and radiation combination treatment in vitro and in vivo compared with individual treatments. Combination treatment also affected the expression of the DNA repair protein H2A histone family member X (γ-H2AX). In conclusion, our results reveal that Icotinib enhances radiosensitivity in lung cancers in vitro and in vivo and the mechanism of this may involve blocking the EGFR-AKT and MAPK-ERK pathways and limiting DNA repair.

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Depletion of Histone Demethylase Jarid1A Resulting in Histone Hyperacetylation and Radiation Sensitivity Does Not Affect DNA Double-Strand Break Repair

Cited by 15 publications

References 95 publications

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

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

JARID1 Histone Demethylases: Emerging Targets in Cancer

Icotinib enhances lung cancer cell radiosensitivity in vitro and in vivo by inhibiting MAPK/ERK and AKT activation

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