IQGAP3 interacts with Rad17 to activate the MRN/ATM/Chk2 signaling and promote radioresistance in lung cancer
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PROVIDER: PRJNA573096 | ENA |
REPOSITORIES: ENA
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Project description:IQ motif containing GTPase activating protein 3 (IQGAP3) has been implicated in diverse cellular processes including neuronal morphogenesis, cell proliferation and motility as well as epithelial-mesenchymal transition. However, its roles in DNA damage and repair remain to be clarified. Here, we demonstrate that IQGAP3 is frequently overproduced and predicts poor prognosis in lung cancer patients. Functionally, we provide evidence that depletion of IQGAP3 impairs tumorigenesis and overcomes radioresistance in lung cancer in vitro and in vivo. Mechanistically, we uncover that IQGAP3 interacts with and controls the stability of Rad17 to activate the ATM/Chk2 signaling by recruiting Mre11-Rad50-Nbs1 (MRN) complex in response to DNA damage. Moreover, Rad17 is identified as the major downstream effector that mediates the functions of IQGAP3 in lung cancer. Clinically, IQGAP3 overexpression positively correlates with Rad17 protein levels in human lung cancer tissues. Collectively, these data support key roles for IQGAP3 in promoting tumorigenesis and radioresistance in lung cancer by stabilizing the Rad17 protein and suggest targeting IQGAP3 is a promising therapeutic strategy for lung cancer radiotherapy.
2019-09-21 | GSE137802 | GEO
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:Background: Cancer cells inevitably develop resistance to radiation in lung cancer radiotherapy. However, the underlying mechanisms remain to be fully clarified. This study aimed to explore the roles and mechanisms of FGF1 intracellular binding protein (FIBP)?in lung cancer radioresistance. Methods: Expression levels of FIBP in human lung cancer and adjacent tissues were analyzed by immunohistochemical (IHC) staining. Cell growth and proliferation, EdU and CFSE assays, Neutral comet and clonogenic survival analysis as well as mouse xenograft model were performed to explore the functions of FIBP in vitro and in vivo. The underlying mechanisms were investigated by RNA sequencing, co-immunoprecipitation and dual luciferase reporter assays. Results: The expression levels of FIBP in lung cancer tissues were significantly upregulated compared with adjacent normal tissues and associated with worse overall survival. Functionally, we found that depletion of FIBP impairs lung cancer progression and radioresistance in vitro and in vivo. Mechanistically, we uncovered that FIBP interacts with STAT3 to enhance the transcriptional activity of STAT3, thereby inducing the expression of downstream target gene Eme1. Importantly, we also demonstrated that the biological effects of FIBP were partially dependent on Eme1 in lung cancer. Conclusions: These results reveal that FIBP modulates STAT3/Eme1 axis to drive lung cancer progression and radioresistance, indicating targeting FIBP may be a novel intervention strategy for lung cancer radiotherapy.
2022-06-06 | GSE196635 | GEO
Project description:Rationale: Radioresistance remains the major cause of local relapse and distant metastasis in lung cancer. However, the underlying molecular mechanisms remain poorly defined. This study aimed to investigate the role and regulatory mechanism of Cyclin K in lung cancer radioresistance. Methods: Expression levels of Cyclin K were measured by immunohistochemistry in human lung cancer tissues and adjacent normal lung tissues. Cell growth and proliferation, neutral comet and foci formation assays, G2/M checkpoint and a xenograft mouse model were used for functional analyses. Gene expression was examined by RNA sequencing and quantitative real-time PCR. Protein-protein interaction was assessed by immunoprecipitation and GST pull-down assays. Results: We report that Cyclin K is frequently overexpressed and correlates with poor prognosis in lung cancer patients. Functionally, we demonstrate that Cyclin K depletion results in reduced proliferation, defective G2/M checkpoint and enhanced radiosensitivity in lung cancer. Mechanistically, we reveal that Cyclin K interacts with and promotes the stabilization of β-catenin, thereby upregulating the expression of Cyclin D1. More importantly, we show that Cyclin D1 is the major effector that mediates the biological functions of Cyclin K in lung cancer. Conclusions: These findings suggest that Cyclin K positively modulates the β-catenin/Cyclin D1 axis to promote tumorigenesis and radioresistance in lung cancer, indicating that Cyclin K may represent a novel attractive biomarker for lung cancer radiotherapy.
2020-01-07 | GSE143147 | GEO
Project description:KDM6B interacts with TFDP1 to activate P53 signalling in regulating mouse palatogenesis
| PRJNA732199 | ENA
Project description:KDM6B interacts with TFDP1 to activate P53 signalling in regulating mouse palatogenesis
| PRJNA732200 | ENA
Project description:KDM6B interacts with TFDP1 to activate P53 signalling in regulating mouse palatogenesis
| PRJNA732201 | ENA
Project description:NK/T cell lymphoma (NKTCL) is a highly aggressive subtype of non-Hodgkin lymphoma. GELOX (gemcitabine, oxaliplatin, and L-asparaginase) is one of the first-line chemotherapy regimens of NKTCL. Yet, the prognosis of NKTCL is poor. Icaritin (ICT) is an herb-derived monomer from icariin with antitumor effects. We found that icaritin induced proliferation inhibition and apoptosis of NKTCL both in vitro and in vivo. Moreover, icaritin inhibited the dissemination of NKTCL in vivo. RNA sequencing (RNA-seq) revealed the polo-like kinase 1 (PLK1) gene and DNA damage response (DDR) as the targets of icaritin. Mechanistically, icaritin inhibited PLK1 to promote checkpoint kinase 2 (Chk2) homodimerization and its T387 phosphorylation, which further activated p53, leading to the activation of the DDR pathway. Moreover, inhibiting PLK1 increased Forkhead box O3a (FOXO3a) nuclear localization, the latter of which activated Ataxia-telangiectasia mutated (ATM), an early sensor of DNA damage. Then ATM phosphorylated Chk2 T68 and initiated Chk2 activation. Remarkably, combined treatment of icaritin and GELOX achieved better antitumor efficacy than single treatment in vivo. In summary, our results proved the efficacy of icaritin treating NKTCL, and provided insights into its antitumor molecular mechanism, and revealed the application value of icaritin in facilitating clinical NKTCL treatment.
2022-05-04 | GSE201959 | GEO
Project description:FIBP interacts with transcriptional factor STAT3 to induce Eme1 expression and drives radioresistance in lung cancer
| PRJNA806645 | ENA
Project description:Homologous recombination-mediated DNA repair deficiency (HRD) predisposes to cancer development, but also provides therapeutic opportunities. Here, we identified an HRD gene signature that robustly predicted HRD status. Unexpectedly, concurrent loss of PTEN in BRCA1-deficient cells might extensively rewire the HR repair network and confer resistance to PARP inhibitor, partially through over-expression of TTK. We used the HRD gene signature as a drug discovery tool and found several PARP-inhibitor-synergizing agents through the connectivity map. Thus gene expression profiling can be used to define the functional status of the HR repair network providing prognostic and therapeutic information. Various shRNAs that target genes involved in homologous recombination (HR) were transfected in MCF-10A non-transformed breast cells lines. Stable HR gene knockdown MCF-10A cells were seeded 200000 at 10 cm plate. Cells were harvested after 48 hours culturing and used for gene expression profiling. The shRNAs that target ATM, ATR, CHK1, CHK2, and 53BP1 genes were transfected in MCF-10A non-transformed breast cell line by lentiviral particles and selected stable ATM, ATR, CHK1, CHK2, and 53BP1 knockdown MCF-10A cells. Scrambled control shRNA-transfected and wild type MCF-10A cells were applying as control. All knockdown and control MCF-10A cells were seeded with 2 x 10^5 cells at 10 cm culture plate. Cells were cultured in MCF-10A medium and harvested after 48 hours culturing. mRNA was extracted from collected cells and performing gene expression profiling. Three biological replicates were applied.
2014-01-24 | E-GEOD-54268 | biostudies-arrayexpress