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:Background: Osteosarcoma, a primary malignant bone tumor predominantly affecting children and adolescents, exhibits a dismal prognosis for patients with metastatic or recurrent disease, characterized by low five-year survival rates. This poor outcome is largely attributed to the incomplete understanding of the molecular mechanisms governing osteosarcoma aggressiveness and metastasis, coupled with a paucity of effective early diagnostic biomarkers and targeted therapeutic strategies. Consequently, elucidating the critical molecular events driving osteosarcoma pathogenesis and identifying novel biomarkers are of paramount importance for improving patient outcomes. Prior research has demonstrated aberrant expression of Zinc Finger DHHC-Type Palmitoyltransferase 9 (ZDHHC9) in various malignancies, but its specific function and clinical significance in osteosarcoma remain poorly defined. Methods: This study employed a comprehensive approach integrating bioinformatic analyses and experimental validation to investigate the functional role and clinical relevance of ZDHHC9 in osteosarcoma. Bioinformatic analyses (TIMER, GEPIA, TCGA databases) were utilized to examine ZDHHC9 expression across a pan-cancer landscape and its association with survival in osteosarcoma patients. Immunohistochemistry (IHC) and Western blotting were employed to analyze ZDHHC9 expression in clinical osteosarcoma specimens and cell lines. In vitro assays (CCK-8, colony formation, wound healing, Transwell, flow cytometry, and Western blotting) were performed to evaluate the impact of ZDHHC9 on osteosarcoma cell proliferation, migration, and invasion. Proteomic sequencing, molecular docking, and co-immunoprecipitation (Co-IP) experiments were conducted to explore the interaction between ZDHHC9 and KRAS. Western blotting was used to analyze the regulation of Raf1, ERK1/2, and p-ERK1/2 expression by ZDHHC9 and KRAS. Finally, a xenograft model was employed to assess the effect of ZDHHC9 on in vivo tumor growth. Results: Bioinformatic analyses revealed that elevated ZDHHC9 expression correlates with poor prognosis in osteosarcoma. IHC and Western blotting confirmed significantly increased ZDHHC9 expression in osteosarcoma tissues compared to adjacent non-tumorous tissues. Upregulation of ZDHHC9 was significantly associated with elevated Ki67 levels and advanced Enneking stage, suggesting a link to tumor aggressiveness. In vitro studies demonstrated that downregulation of ZDHHC9 suppressed osteosarcoma cell proliferation, migration, and invasion, while promoting apoptosis. Conversely, upregulation of ZDHHC9 elicited opposite effects. Proteomic sequencing revealed that ZDHHC9 knockdown significantly downregulated the expression of proteins associated with the RAS/MAPK signaling pathway. Functional experiments showed that overexpression of KRAS partially abrogated the inhibitory effects of ZDHHC9 knockdown on cell proliferation, migration, and invasion. Molecular docking and Co-IP experiments confirmed a specific interaction between ZDHHC9 and KRAS, leading to activation of the RAS/MAPK signaling pathway. Conclusion: ZDHHC9 promotes osteosarcoma cell proliferation, migration, and invasion by enhancing KRAS-mediated activity of the RAS/MAPK signaling pathway, which promotes cell cycle progression while inhibiting apoptosis.
2025-10-27 | PXD066322 | Pride
Project description:Osteosarcoma is the most common malignant bone tumor in children and adolescents. Osteosarcoma has a strong tendency of lung metastasis and patients with metastases have poor prognoses. Lactate Dehydrogenase A subunit (LDHA) is one of the key enzymes in glycolysis and is known to be involved in progression and metastases of various cancers. Here, we showed that Ldha knockdown suppressed cell migration and invasion in vitro in murine osteosarcoma cells and decreased lung metastases in vivo. Subsequent RNA-seq analysis revealed that Ldha knockdown was associated with downregulation of the Hedgehog signaling pathway and we demonstrated that pharmacological inhibition of the Hedgehog signaling pathway with vismodegib also suppressed cell migration, invasion and lung metastases in murine osteosarcoma cells as well as Ldha knockdown. Furthermore, in human osteosarcoma cells, we confirmed that LDHA silencing led to the downregulation of the Hedgehog signaling pathway and that cell migration and invasion were suppressed by inhibiting the Hedgehog signaling pathway. Collectively, we elucidated that Ldha-Hedgehog signaling pathway axis is involved in osteosarcoma lung metastases. Our findings might contribute to further understanding for the molecular mechanism of osteosarcoma lung metastases and the development of a novel therapy for them.
2026-05-28 | GSE288144 | 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: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:Arginine methylation is a common posttranslational modification that is catalyzed by a family of protein arginine methyltransferases. Recognition of methylarginine marks by effector proteins (“readers”) is a critical link between arginine methylation and various cellular processes. We recently identified methylation of AKT1 at Arg391 by PRMT5, but the reader for this methylation has yet to be characterized. Here, we show that BRD9, a reader of acetylated lysine, unexpectedly recognizes Arg391-methylated AKT1 through an aromatic cage in its bromodomain. Disrupting the methylarginine reader function of BRD9 suppresses AKT activation and tumorigenesis. RNA-sequencing data shows that BRD9 and AKT co-regulate a hallmark transcriptional program in part through EZH2-mediated H3K27 trimethylation. Lastly, we find that inhibitors of BRD9 and EZH2 display synergistic effects on inhibition of cell viability and tumor growth. Together, our study demonstrates that BRD9 serves as a methylarginine reader to promote AKT-EZH2 oncogenic signaling and combined inhibition of BRD9 and EZH2 is a potential strategy for cancer therapy.
2025-03-18 | PXD058540 | Pride
Project description:Chemoresistance remains a major challenge in osteosarcoma therapy, severely limiting the efficacy of cisplatin-based chemotherapy. Here, we identify the palmitoyltransferase ZDHHC8 as a critical determinant of cisplatin resistance and uncover a lipid modification–dependent mechanism that stabilizes β-catenin and sustains WNT signaling. ZDHHC8 expression was markedly upregulated in chemoresistant osteosarcoma tissues, and its knockdown significantly enhanced cisplatin-induced apoptosis both in vitro and in vivo. Transcriptomic profiling and functional assays revealed that ZDHHC8 depletion suppressed WNT/β-catenin signaling and diminished cancer stem cell–like properties. Mechanistically, ZDHHC8 directly interacted with β-catenin and catalyzed its C381-specific palmitoylation, which prevented proteasomal degradation and maintained protein stability. Mutation of C381 abolished β-catenin palmitoylation, resulting in reduced WNT activity and impaired stemness maintenance. Conversely, ZDHHC8 overexpression stabilized β-catenin and conferred cisplatin resistance. Collectively, our findings reveal a previously unrecognized ZDHHC8–β-catenin palmitoylation axis that governs WNT pathway activation and osteosarcoma chemoresistance. Targeting ZDHHC8 or disrupting β-catenin palmitoylation offers a promising therapeutic strategy to overcome drug resistance and improve osteosarcoma outcomes.
2026-07-01 | GSE317900 | GEO
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:Post-transcriptional regulation mediated by RNA-binding proteins is essential for B cell development and differentiation. EZH2 is a key regulatory protein involved in B cell development and the germinal center response, and its expression is subject to alternative splicing regulation. Skipping of exon 14 in EZH2 disrupts its catalytic activity for H3K27me3 deposition. To identify proteins that regulate EZH2 alternative splicing in B cells, we performed an RNA pull-down assay using exon 14 together with part of intron 14 of EZH2 pre-mRNA, followed by mass spectrometry analysis of the pulled-down proteins.
2026-04-30 | PXD077818 | Pride