KDM4C silencing inhibits cell migration and enhances radiosensitivity by upregulating CXCL2 in hepatocellular carcinoma
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ABSTRACT:
PROVIDER: PRJNA785182 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17085078_1.fastq.gz | Fastqsanger.gz | |||
| SRR17085078_2.fastq.gz | Fastqsanger.gz | |||
| SRR17085079_1.fastq.gz | Fastqsanger.gz | |||
| SRR17085079_2.fastq.gz | Fastqsanger.gz | |||
| SRR17085080_1.fastq.gz | Fastqsanger.gz |
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Project description:KDM4C, a histone lysine demethylase, has been proposed to participate in malignant transformation and progression in several types of cancer. However, its roles in hepatocellular carcinoma (HCC) remain poorly understood. In this study, we report that KDM4C protein level is upregulated and KDM4C silencing inhibits cell growth, proliferation and migration in HCC. Furthermore, we provide evidence that depletion of KDM4C leads to defective G2/M checkpoint, increases radiation-induced DNA damage and impairs DNA repair, and enhances radiosensitivity in HCC cells. Using RNA sequencing, we uncover that chemokine CXCL2 is a downstream effector of KDM4C. KDM4C knockdown upregulates the expression of CXCL2 and promotes the secretion of CXCL2 in HCC cells. Importantly, the observed effects caused by KDM4C depletion in HCC cells can be partially rescued by CXCL2 silencing. Thus, our findings demonstrate that KDM4C is involved in the cell migration and radiosensitivity via modulating CXCL2, indicating that KDM4C may be a potential therapeutic target in HCC.
2023-05-03 | GSE189941 | GEO
Project description:KDM4C, which is a histone lysine demethylase, has been proposed to participate in the malignant transformation and progression of several types of cancer. However, its roles in hepatocellular carcinoma (HCC) remain poorly understood. Here, we find that KDM4C protein expression is increased in HCC and promotes HCC cell growth, proliferation and migration. Furthermore, we provide evidence that depletion of KDM4C leads to a defective G2/M checkpoint, increases radiation-induced DNA damage, impairs DNA repair and enhances radiosensitivity in HCC cells. Using RNA sequencing, we identify that the chemokine CXCL2 is a downstream effector of KDM4C. KDM4C knockdown increases the binding of H3K36me3 to the promoter of CXCL2, thus upregulating CXCL2 expression and promoting CXCL2 secretion in HCC cells. Importantly, the observed effects of KDM4C depletion in HCC cells can be partially rescued by CXCL2 silencing. Thus, our findings reveal that KDM4C is involved in cell migration and radiosensitivity by modulating CXCL2 transcription, indicating that KDM4C may be a potential therapeutic target in HCC.
| S-EPMC10147924 | biostudies-literature
Project description:The use of checkpoint blockade immunotherapy has revolutionized the field of cancer therapy. Although Immune checkpoint blockade (ICB) can achieve persistent response in several cancers, only 20-40% of patients can benefit from this therapeutic method. Preclinical and clinical evidence show that Radiotherapy (RT) can enhance tumor immunogenicity and improve the effects of immune checkpoint inhibitors. However, the actual outcomes are not satisfactory. Our previous studies revealed that the oncogene, Lysine-specific demethylase 4C (KDM4C) could regulate the radiosensitivity of lung cancer cells in vitro and in vivo. However, the role of KDM4C in antitumor immunity remains inconclusive. To that end, we analyzed the composition of infiltrating immune cells in our mouse tumor model using flow cytometry and found that KDM4C silencing could promote the intratumoral infiltration of CD8+ T cells. Further functional analysis showed that KDM4C silencing could promote proliferation, migration and activation of CD8+ T cells in vivo and in vitro and delay CD8+ T cells exhaustion. Mechanistically, using RNA-seq and Chip-PCR analysis, we determined that KDM4C silencing promotes the binding of H3K36me3 to the Cxcl10 promoter region to increase its transcriptional activity and thus induce CD8+ T cell-mediated antitumor response. Our results suggest that KDM4C-specific inhibitor, SD70 can reprogram the epigenetic state and improve the tumor microenvironment. More importantly, we found that the combined use of SD70, RT, and PD-L1 monoclonal antibodies exhibited the strongest antitumor effects and prolonged the survival time of tumor-bearing mice. Together, our findings suggest that a combination of KDM4C-targeted treatment, radiotherapy, and immune checkpoint blockade is safe and efficient for treating lung cancer.
2022-02-18 | GSE178177 | GEO
Project description:In this study, we performed RNA-seq in GFP-VSV infected mouse lung epithelial cell lines (MLE-12 cells) and found that the expression of a non-coding RNA was increased upon VSV infection in Cxcl2 locus, which we termed it as lnc-Cxcl2. We further detected the function of lnc-Cxcl2 by performing transcriptome analysis in lnc-Cxcl2-deficient MLE-12 cells with and without VSV infection, and found that lnc-Cxcl2 suppressed Cxcl2 expression in MLE-12 cells with and without VSV infection.
2021-09-26 | GSE156949 | GEO
Project description:lnc-Cxcl2 suppressed Cxcl2 expression in mouse lung epithelial cells
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Project description:Gastric cancer (GC) stem cells (GCSCs) are characterized as high level of ALDH activity, however, the mechanisms of maintenance of high ALDH activity and stemness in GCSCs are largely unknown. Here, we report that KDM4C, a H3K9me2/3-demethylase, epigenetically regulates ALDH1A3 by histone demethylation and forms a feed-forward loop with ALDH1A3 to supports GS stemness. Ectopic expression of both KDM4C and ALDH1A3 promotes the properties of GCSCs, including spherogenecity, self-renewal, CD44 expression and ALDH activity; knockdown of anyone abolished the effect of each other. KDM4C directly binds to the promoter of ALDH1A3, leads to histone demethylation, thereby promoting ALDH1A3 transcription. Upregulated ALDH1A3 in turn transcriptionally upregulates KDM4C. Simultaneous inhibition of KDM4C and ALDH1A3 synergistically sensitizes GC sphere-derived cells to traditional chemotherapeutic drugs. The finding that upregulated ALDH1A3 promotes its own transcription via KDM4C-mediated epigenetic modification represents an important feed-forward mechanism for GCSCs to maintain stemness and promote tumourigenesis and our work thus suggests a novel therapeutic strategy for eradicating human GCSCs. To investigate the mechanisms underlying KDM4C promoting CG stemness, we identified the differentially expressed proteins (DEPs) between KDM4C-overexpressing and control AGS cells by iTRAQ-based quantitative proteomic analysis.
2022-02-16 | PXD023455 | Pride
Project description:MIR193BHG inhibits the proliferation, migration and invasion of trophoblasts by upregulating p53
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Project description:Epigenetic and genetic regulations are sometimes considered as separate mechanisms that influence gene expression and phenotypes. However, there are DNA sequence variants in epigenetic regulators that could affect gene regulation. The histone demethylase, KDM4C, promotes transcriptional activation by removing the repressive histone mark, tri-methylation of lysine 9 of histone H3 (H3K9me3), from its target genes. In this study, we uncovered cis-acting DNA sequence variants in KDM4C that contribute to individual differences in its expression. Utilizing this natural variation, we performed genetic analyses in B-cells in order to identify target genes that are regulated by KDM4C. We used microarrays to investigate gene expression changes in the target genes from our genetic analyses following knockdown of KDM4C in primary fibroblasts. Primary fibroblasts with stable expression of shRNA targeting KDM4C or a control construct were selected for RNA extraction and hybridization to Affymetrix microarrays. Following selection for stable expression of the shRNA constructs we selected clones expressing 3 non-overlapping constructs targeting KDM4C (shKDM4C) and 2 clones expressing the control construct (shCtr) for analysis by microarray.
2013-09-14 | E-GEOD-41040 | biostudies-arrayexpress
Project description:Radioresistance is regarded as the main barrier to effective radiotherapy in lung cancer. However, the underlying mechanisms of radioresistance remain elusive. Here, we show that lysine-specific demethylase 4C (KDM4C) is overexpressed and correlated with poor prognosis in lung cancer patients. We provide evidence that genetical or pharmacological inhibition of KDM4C impairs tumorigenesis and radioresistance in lung cancer in vitro and in vivo. Moreover, we uncover that KDM4C upregulates TGFβ2 expression by directly reducing H3K9me3 level at the TGFβ2 promoter and then activates TGF-β/Smad/ATM signaling to confer radioresistance in lung cancer. Using tandem affinity purification technology, we further identify deubiquitinase USP9X as a critical binding partner which deubiquitinates and stabilizes KDM4C. More importantly, depletion of USP9X impairs TGF-β/Smad signaling and radioresistance by destabilizing KDM4C in lung cancer cells. Thus, our findings demonstrate that USP9X-mediated KDM4C deubiquitination activates TGF-β/Smad signaling to promote radioresistance, suggesting that targeting KDM4C may be a promising radiosensitization strategy in the treatment of lung cancer.
2021-07-14 | GSE136404 | GEO
Project description:Epigenetic and genetic regulations are sometimes considered as separate mechanisms that influence gene expression and phenotypes. However, there are DNA sequence variants in epigenetic regulators that could affect gene regulation. The histone demethylase, KDM4C, promotes transcriptional activation by removing the repressive histone mark, tri-methylation of lysine 9 of histone H3 (H3K9me3), from its target genes. In this study, we uncovered cis-acting DNA sequence variants in KDM4C that contribute to individual differences in its expression. Utilizing this natural variation, we performed genetic analyses in B-cells in order to identify target genes that are regulated by KDM4C. We used microarrays to investigate gene expression changes in the target genes from our genetic analyses following knockdown of KDM4C in primary fibroblasts.
2013-09-14 | GSE41040 | GEO