IL11RA signaling and EZH2 activity in osteosarcoma
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ABSTRACT:
PROVIDER: PRJNA790619 | ENA |
REPOSITORIES: ENA
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Project description:Lung metastasis is the principal cause of death by osteosarcoma (OS), and has been shown by in vivo modeling to depend on interleukin-11 receptor alpha (IL11RA). To investigate IL11RA signaling in OS, we determined the effects of IL11RA knockdown on gene expression in the OS cell line KRIB. Increased expression of genes repressed by the methyltransferase EZH2 was observed after IL11RA knockdown. Subsequent studies confirmed that IL11RA signaling promotes EZH2 activity and lung metastasis in OS.
2022-03-01 | GSE191215 | GEO
Project description:CNTNAP4 signaling regulates osteosarcoma disease progression
| PRJNA865383 | ENA
Project description:Cancer is a global leading cause of death, with nearly 10 million people dying from cancer in 2020. Photodynamic therapy (PDT) has emerged as a promising cancer treatment modality; however, the potential molecular mechanisms remain obscure. Herein, we designed a near-infrared (NIR) light-activated nanoplatform (TPBC-PEG) to explore the therapeutic effects and mechanisms of PDT by using a model of intratibial primary and pulmonary metastasis osteosarcoma. Under laser irradiation, TPBC-PEG photosensitizer dose-dependently inhibited proliferative and metastatic capability while promoting apoptosis of osteosarcoma cells in vitro, and also effectively suppressed carcinogenesis and pulmonary metastasis in osteosarcoma xenograft mouse model. Moreover, the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis after high-throughput mRNA-seq indicated that the HIPPO signaling pathway was one of the 20 most significantly related signaling pathways. And a series of experiments for determining the HIPPO signaling activity were conducted to reconfirm the specificity. Collectively, PDT of TPBC-PEG micelles against carcinogenesis and pulmonary metastasis of deep-seated intratibial osteosarcoma was achieved by activating HIPPO signaling pathway. Our study identified a hitherto uncharacterized molecular mechanism of PDT, which may provide new insights to understand and design promising nanoplatforms for future cancer therapies.
2023-08-25 | GSE211393 | GEO
Project description:The regulation of gene expression through histone post-translational modifications plays a crucial role in breast cancer progression. However, the molecular mechanisms underlying the contribution of histone modification to tumor initiation remain unclear. To gain a deeper understanding of the role of the histone modifier Enhancer of Zeste homology 2 (Ezh2) in the early stages of mammary tumor progression, we employed an inducible mammary organoid system bearing conditional Ezh2 alleles that faithfully recapitulates key events of Luminal B breast cancer initiation. We showed that the loss of Ezh2 severely impairs oncogene-induced organoid growth, with Ezh2-deficient organoids maintaining a polarized epithelial phenotype. Transcriptomic profiling showed that Ezh2-deficient mammary epithelial cells upregulated the expression of negative regulators of Wnt signaling and downregulated genes involved in mTORC1 (mechanistic target of rapamycin complex 1) signaling. We identified Sfrp1, a Wnt signaling suppressor, as an Ezh2 target gene that is de-repressed and expressed in Ezh2-deficient epithelium. Furthermore, an analysis of breast cancer data revealed that Sfrp1 expression was associated with favorable clinical outcomes in Luminal B breast cancer patients. Finally, we confirmed that targeting Ezh2 impairs mTORC1 activity through an indirect mechanism that upregulates the expression of the tumour suppressor Pten. These findings indicate that Ezh2 integrates the mTORC1 and Wnt signaling pathways during early mammary tumor progression, arguing that inhibiting Ezh2 or therapeutically targeting Ezh2-dependent programs could be beneficial for the treatment of early-stage Luminal B breast cancer.
2023-07-15 | GSE235144 | GEO
Project description:Overexpression of EZH2 in estrogen receptor negative (ER-) breast cancer promotes metastasis. EZH2 has been mainly studied as the catalytic component of the Polycomb Repressive Complex 2 (PRC2) that mediates gene repression by trimethylating histone H3 at lysine 27 (H3K27me3). However, how EZH2 drives metastasis despite the low H3K27me3 levels observed in ER- breast cancer is unknown. We have shown that in human invasive carcinomas and distant metastases, cytoplasmic EZH2 phosphorylated at T367 is significantly associated with ER- disease and low H3K27me3 levels. Here, we explore the interactome of EZH2 and of a phosphodeficient mutant EZH2_T367A. We identified novel interactors of EZH2, and identified interactions that are dependent on the phosphorylation and cellular localization of EZH2 that may play a role in EZH2 dependent metastatic progression.
2018-07-03 | PXD010073 | Pride
Project description:DNA repair dysregulation is a key driver of cancer development. Understanding the molecular mechanisms underlying DNA repair pathways and their dysregulation in cancer cells is crucial for cancer development and therapies. Here, we report that enhancer of zeste homolog 2 (EZH2) directly methylates poly (ADP-ribose) polymerase-1 (PARP-1), an essential enzyme involved in DNA repair, at lysine 607 and regulates its activity. Functionally, EZH2-catalyzed methylation represses PARP1 catalytic activity, inhibits the recruitment of X-ray repair cross-complementing group-1 (XRCC1) recruitment to DNA lesions and hence impairs DNA damage repair. Meanwhile, EZH2-mediated methylation regulates PARP1 transcriptional and oncogenic activity, at least in part, through impairing PARP1-E2F1 interaction and E2F1 transcription factor activity. Collectively, our findings uncover a novel insight of EZH2 functions in DNA damage repair and cancer progression, which provides a new rationale for combinational targeting EZH2 and PARP1 in cancer.
2024-08-01 | GSE239560 | GEO
Project description:Purpose: To understand the mechanism of lobaplatin resistance and explore effective strategies for patients with osteosarcoma. Results: The expression of FUBP1 was remarkably elevated in osteosarcoma cell lines and clinical specimens compared with osteoblast cells and the normal bone. High expression of FUBP1 correlated with more aggressive phenotype and poor prognosis in osteosarcoma patients. Overexpression of FUBP1 confers lobaplatin resistance while inhibition of FUBP1 sensitizes osteosarcoma to lobaplatin cytotoxicity both in vivo and in vitro. Additionally, FUBP1 could regulate the transcription of PTGES, and subsequently activated the arachidonic acid signaling pathway in osteosarcoma cells treated with lobaplatin. Conclusions: Our investigation provided evidence that FUBP1 represents a potential therapeutic target for patients suffering from osteosarcoma. Targeting FUBP1 and its downstream AA signaling pathway may be a promising strategy to sensitize lobaplatin treatment during osteosarcoma chemoresistance. Methods: The expression of Far upstream element-binding protein 1(FUBP1) in human osteosarcoma cell lines and patient specimens were determined using Western blotting and Real-time PCR, respectively. 61 human osteosarcoma tissue specimens were analyzed using IHC to investigate the association between the expression of FUBP1 and the clinicopathological data of osteosarcoma patients. CCK8, FACS, clone formation assay, and in vivo animal xenograft model were used to determine the role of FUBP1 in lobaplatin-treating osteosarcoma. ChIP-seq and RNA-seq were performed, and the intersection genes and the enriched signaling pathways were analyzed. Luciferase assay and truncation assay were used to investigate the mechanism of FUBP1 promoting chemoresistance in osteosarcoma.
2023-05-17 | GSE210740 | GEO
Project description:Osteosarcoma is a prevalent primary malignant bone tumor in children and young adults, with limited progress in improving survival rates for metastatic or recurrent cases. Kinase inhibitors emerged as potential treatment for osteosarcoma due to the critical role of kinases regulating network. However, single-agent kinase inhibitors often face challenges due to the activation of compensatory oncogenic signaling pathways, which can undermine treatment efficacy. In this study, a systematic combination screening of kinase inhibitors was further conducted in osteosarcoma cells. Among 190 pair-wise combinations, 44 exhibited strong synergistic antitumor efficacy. Notably, the combination of the ALK inhibitor Ceritinib and the FLT3 inhibitor Crenolanib showed significant synergistic effects against osteosarcoma cell lines, patient-derived organoids in vitro, and xenograft models in vivo. This combination also effectively mitigated the compensatory activation of oncogenic signaling pathways, a common resistance mechanism to single-agent therapies. Our findings provide compelling evidence that dual kinase inhibition targeting ALK and FLT3 can effectively exploit pharmacological vulnerabilities in osteosarcoma, suggesting a promising therapeutic strategy for clinical application. This combinatorial approach could potentially overcome the limitations of single-agent therapies and improve outcomes for patients with osteosarcoma. Further clinical evaluation is warranted to confirm these preclinical results.
2024-10-29 | GSE278302 | GEO
Project description:EZH2 induces active transcription of the AR gene, thereby increasing AR level and promoting AR signaling. Importantly, EZH2-mediated activation of AR requires EZH2 protein occupancy at the AR gene promoter, but is independent of PRC2 as well as its histone methyltransferase activity
2018-12-01 | GSE107780 | GEO
Project description:The responses of macrophages to lipopolysaccharide (LPS) might determine the direction of clinical manifestations of sepsis, which is the immune response against severe infection. Meanwhile, the enhancer of zeste homologue 2 (Ezh2), a histone lysine methyltransferase of epigenetic regulation, might interfere with LPS response. With a single LPS stimulation, Ezh2 null(Ezh2flox/flox; LysM-Crecre/−) macrophages demonstrated lower supernatant TNF-α than Ezh2 control (Ezh2fl/fl; LysM-Cre−/−), perhaps due to an upregulation of Socs3, which is a suppressor of cytokine signaling 3, due to the loss of the Ezh2 gene. In LPS tolerance, Ezh2 null macrophages indicated higher supernatant TNF-α and IL-6 than the control, supporting an impact of the loss of the Ezh2 inhibitory gene. In parallel, Ezh2 null mice demonstrated lower serum TNF-α and IL-6 than the control mice after an LPS injection, indicating a less severe LPS-induced hyper-inflammation in Ezh2 null mice. In conclusion, an absence of Ezh2 in macrophages resulted in less severe LPS-induced inflammation, as indicated by low serum cytokines, with less severe LPS tolerance, as demonstrated by higher cytokine production, partly through the upregulated Socs3.
2023-07-20 | PXD041265 | Pride