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

Pippa, Simone; Mannironi, Cecilia; Licursi, Valerio; Bombardi, Luca; Colotti, Gianni; Cundari, Enrico; Mollica, Adriano; Coluccia, Antonio; Naccarato, Valentina; Regina, Giuseppe La; Silvestri, Romano; Negri, Rodolfo

doi:10.3390/molecules24091739

Cited by 31 publications

(28 citation statements)

References 69 publications

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“…Knockdown of these proteins decreases the ability of cells to repair their damaged DNA (25)(26)(27). Similarly, small molecule inhibitors of KDM5 enzymes increase the levels of H3K4me3 chromatin modification which in turn leads to impaired DNA repair through both homologous recombination and non-homologous end joining (28,51). Our data are in agreement with these observations.…”

Section: Discussionsupporting

confidence: 89%

ASH2L drives proliferation and sensitivity to bleomycin and other genotoxins in Hodgkin’s lymphoma and testicular cancer cells

Constantin

Widmann

2020

Preprint

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It is of clinical importance to identify biomarkers predicting the efficacy of DNA damaging drugs (genotoxins) so that non-responders are not unduly exposed to the deleterious effects of otherwise inefficient drugs. Using a whole genome CRISPR/Cas9 gene knockout approach we have identified that low levels of ASH2L cause resistance to genotoxins. ASH2L is a core component of the H3K4 methyl transferase complex. We show that ASH2L absence decreases cell proliferation and favors DNA repair upon genotoxin exposure. The cell models we have used are derived from cancers currently treated either partially (Hodgkin’s lymphoma), or entirely (testicular cancer) with genotoxins. For such cancers, ASH2L levels could be used as a biomarker to predict the response to genotoxins. Our data also indicate that patients with low ASH2L expressing tumors do not develop resistance to ATR inhibitors. In these patients, such inhibitors may represent an alternative treatment to DNA damaging drugs.

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Section: Discussionsupporting

confidence: 89%

ASH2L drives proliferation and sensitivity to bleomycin and other genotoxins in Hodgkin’s lymphoma and testicular cancer cells

Constantin

Widmann

2020

Preprint

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“…Moreover, specific inhibitory drugs have been developed and are currently in pre-clinical trials, including EPT103182, a KDM5 inhibitor in hematological cancers, such as multiple myeloma, and GSK-J1, a KDM6 inhibitor, in glioma, both with high efficacy against cancer cells [97,99] (Table 1). RS compounds were suggested to increase breast cancer cells sensitivity to RT, affecting DNA repair mechanisms [100] (Table 1). Additionally, KDM6 subfamily inhibitors, such as GSK-J1/J4, also enhanced glioblastoma cells radiosensitivity, as well as, in breast and lung adenocarcinoma cell lines [99] (Table 1).…”

Section: Emerging Novel Therapeutic Targets Through Epigenetic Chrmentioning

confidence: 99%

The Critical Role of Hypoxic Microenvironment and Epigenetic Deregulation in Esophageal Cancer Radioresistance

Macedo-Silva

Miranda-Gonçalves

Henrique

et al. 2019

Genes

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Esophageal cancer (EC) is the seventh most common cancer worldwide and the sixth leading cause of death, according to Globocan 2018. Despite efforts made for therapeutic advances, EC remains highly lethal, portending a five-year overall survival of just 15–20%. Hence, the discovery of new molecular targets that might improve therapeutic efficacy is urgently needed. Due to high proliferative rates and also the limited oxygen and nutrient diffusion in tumors, the development of hypoxic regions and consequent activation of hypoxia-inducible factors (HIFs) are a common characteristic of solid tumors, including EC. Accordingly, HIF-1α, involved in cell cycle deregulation, apoptosis, angiogenesis induction and proliferation in cancer, constitutes a predictive marker of resistance to radiotherapy (RT). Deregulation of epigenetic mechanisms, including aberrant DNA methylation and histone modifications, have emerged as critical factors in cancer development and progression. Recently, interactions between epigenetic enzymes and HIF-1α transcription factors have been reported. Thus, further insight into hypoxia-induced epigenetic alterations in EC may allow the identification of novel therapeutic targets and predictive biomarkers, impacting on patient survival and quality of life.

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“…Evidence is emerging that JARID1B contribute to the epigenetic plasticity that underlies malignant transformation [24]. Studies have also shown that JARID1B is an overexpression in numerous cancers [25], JARID1B overexpression is associated with a poor prognosis in breast and prostate cancers [26,27]. Having studies shown that histone demethylase JARID1B associated with CRC cells growth [28].…”

Section: Discussionmentioning

confidence: 99%

JARID1B promotes colorectal cancer proliferation and Wnt/β-catenin signaling via decreasing CDX2 level

Huang

Xiao

Hua

et al. 2020

Preprint

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Background: Jumonji AT-rich interactive domain 1B(JARID1B) has been shown to be upregulated in many human cancers and plays a critical role in the development of cancers cells. Nevertheless, its functional role in colorectal cancer (CRC) progression is not fully understood. Methods: Herein, JARID1B expression levels were detected in clinical CRC samples by western blotting and qRT-PCR. DLD-1 cells with JARID1B knockdown or overexpression by stably transfected plasmids were used in vitro and in vivo study. Colony formation, 5-ethynyl-20-deoxyuridine (EdU) and Real Time Cellular Analysis(RTCA) assays were used to detect cell proliferation and growth. Transcriptome and CHIP assays were used to examine the molecular biology changes and molecular interaction in these cells. Nude mice was utilized to study the correlation of JARID1B and tumor growth in vivo. Results: Here, we first observed that JARID1B was significantly upregulated in CRC tissue compared to adjacent normal tissues. In CRC patients, JARID1B high expression was positively relation with poor overall survival. Multivariate analyses revealed that high JARID1B expression was an independent predictive marker for the poor prognosis of CRC. In addition, we found that JARID1B promoted CRC cells proliferation by Wnt/β-catenin signaling pathway. Further studies demonstrated CDX2 as a downstream target of JARID1B, and our data demonstrated that CDX2 is crucial for JARID1B -mediated Wnt/β-catenin signaling pathway. Mechanistically, we demonstrated that JARID1B regulated CDX2 expression through demethylation of H3K4me3. Conclusions: CDX2 inhibited by JARID1B-derived H3K4me3 methylation promoted cells proliferation of CRC via Wnt/β-catenin signaling pathway. Therefore, our studies provided a novel insight into the role of JARID1B in CRC cells proliferation and potential new molecular target for treating CRC.

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

Cited by 31 publications

References 69 publications

ASH2L drives proliferation and sensitivity to bleomycin and other genotoxins in Hodgkin’s lymphoma and testicular cancer cells

ASH2L drives proliferation and sensitivity to bleomycin and other genotoxins in Hodgkin’s lymphoma and testicular cancer cells

The Critical Role of Hypoxic Microenvironment and Epigenetic Deregulation in Esophageal Cancer Radioresistance

JARID1B promotes colorectal cancer proliferation and Wnt/β-catenin signaling via decreasing CDX2 level

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