Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA238057 | ENA |
REPOSITORIES: ENA
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Project description:Osteosarcoma is the third most common cancer in adolescence and the first common primary malignant tumor of bone. The long-term prognosis of osteosarcoma, especially for unresectable and metastatic tumors, still remains unsatisfactory in the past decades. In this study, we systematically investigated the antitumor effect of imperatorin (IMP), a small molecule extracted from Angelica dahurica, in human osteosarcoma cells. The results showed that IMP triggered time-dependent and dose-dependent inhibition of tumor growth mainly by inducing autophagy promotion and G0/G1 phase arrest in vitro and in vivo. Besides, IMP treatment elevated the expression level of PTEN and p21, down-regulated the phosphorylation of AKT and mTOR. In contrast, the inhibition of PTEN using Bpv (HOpic), a potential and selective inhibitor of PTEN, concurrently rescued IMP-induced autophagy promotion, cell cycle arrest and inactivation of PTEN-PI3K-AKT-mTOR/p21 pathway. Taken together, our data revealed that imperatorin induced autophagy and cell cycle arrest through PTEN-PI3K-AKT-mTOR/p21 signaling pathway by targeting and up-regulating PTEN in human osteosarcoma cells. Hence, imperatorin is a desirable candidate for clinical treatments of osteosarcoma.
2021-12-23 | GSE180321 | GEO
Project description:Glioblastoma ranks among the most aggressive and lethal of all human cancers, with poor responses to all therapeutic modalities. Self-renewing, highly tumorigenic glioblastoma stem cells (GSCs) contribute to therapeutic resistance and maintain cellular heterogeneity. Identification of GSC vulnerabilities may provide novel therapeutic targets for treating glioblastoma. Here, we interrogated superenhancer landscapes of primary glioblastoma specimens and patient-derived GSCs, revealing a kelch domain-containing gene (KLHDC8A) with a previously unknown function as an epigenetically driven oncogene. Targeting KLHDC8A decreased GSC proliferation, reduced sphere formation, induced apoptosis, and impaired in vivo tumor growth. Transcription factor control circuitry analyses revealed that the master transcriptional regulator SOX2 contributes to KLHDC8A expression. Mechanistically, KLHDC8A functions in the assembly of primary cilia via interactions with Chaperonin-containing TCP1 (CCT) and establishes a platform for a critical stem-specific signaling node through the Hedgehog pathway. Furthermore, we identified that Hedgehog and Aurora B/C Kinase signaling are complementary in GSCs, and dual inhibition synergistically inhibits GSC proliferation. Collectively, superenhancers enrich for essential mediators of cellular identity and offer a novel regulatory mechanism whereby promotion of ciliogenesis establishes and maintains a core GSC signaling node via the Hedgehog pathway, potentially offering insights into therapeutic vulnerabilities for glioblastoma treatment.
2022-12-22 | GSE207760 | GEO
Project description:Older age is a major risk factor for damage to many tissues, including liver. Aging undermines resiliency (i.e., the ability to recover from injury) and impairs liver regeneration. The mechanisms whereby aging reduces resiliency are poorly understood. Hedgehog is a signaling pathway with critical mitogenic and morphogenic functions during development. Recent studies indicate that Hedgehog regulates metabolic homeostasis in adult liver. The present study evaluates the hypothesis that Hedgehog signaling becomes dysregulated in hepatocytes during aging, resulting in decreased resiliency and therefore, impaired regeneration and enhanced vulnerability to damage. Methods: Partial hepatectomy (PH) was performed on young and old wild type mice and Smoothened (Smo)-floxed mice treated with AAV8-TBG luciferase (control) or AAV8-TBG-Cre vectors to conditionally delete Smo and disrupt Hedgehog signaling specifically in hepatocytes. Changes in signaling were correlated with changes in regenerative responses and compared among groups. Results: Old livers had fewer hepatocytes proliferating after PH. RNA sequencing identified Hedgehog as a top down-regulated pathway in old hepatocytes before and after the regenerative challenge. Deleting Smo in healthy young hepatocytes before PH prevented Hedgehog pathway activation after PH and inhibited regeneration. GO analysis demonstrated that both old and Smo-deleted young hepatocytes had activation of pathways involved in innate immune responses and suppression of several signaling pathways that control liver growth and metabolism including insulin-like growth factor, Wnt and NOTCH. Hedgehog inhibition promoted telomere shortening and mitochondrial dysfunction in hepatocytes, consequences of aging that promote inflammation and impair tissue growth and metabolic homeostasis. Conclusion: Hedgehog signaling is dysregulated in old hepatocytes. This accelerates aging, resulting in decreased resiliency and therefore, impaired liver regeneration and enhanced vulnerability to damage.
2021-10-15 | GSE181761 | GEO
Project description:Analysis of gene expression levels in response to inhibition of Hh signaling in ovarian and glioma cancer cells using a cDNA microarray technique. Microarray analyses revealed that differentially expressed genes (DEGs) in human cancer cells are enriched in the senescence and autophagy pathways in response to the inhibition of Hh signaling. Further investigations showed that inhibition of Hh signaling induced autophagy.. ES2 and H4 cells were treated with GANT61 (20 M-NM-<M for 32hr and 48hr) and control vehicle DMSO, respectively.
2014-06-15 | E-GEOD-54936 | biostudies-arrayexpress
Project description:CDK7 Inhibition by THZ1 Suppresses Cancer Stemness in both Chemonaïve and Chemoresistant Urothelial Carcinoma via the Hedgehog Signaling Pathway
| PRJNA690137 | ENA
Project description:Resistance to clinically available targeted drugs has become a critical issue in hedgehog-driven cancer treatment. Our previous studies have demonstrated two epigenetic/transcriptional targeted therapeutic strategies, BET inhibition and CDK7 inhibition, could overcome both primary and acquired resistance to Smoothened inhibitor (SMOi) drugs, providing a promising direction for novel anti-hedgehog drug development. In this study, we performed CRISPR-Cas9 screening of epigenetic/transcriptional targeted sgRNA library in hedgehog-driven medulloblastoma (SHH-MB) cells and combined with tumor dataset analyses to identify other potential epigenetic/transcriptional targeted strategies for treating aberrant hedgehog pathway and overcoming SMOi-resistance. Our results demonstrated structure specific recognition protein 1 (SSRP1), a subunit of Facilitates Chromatin Transcription (FACT) complex, was a hedgehog-induced essential oncogene and therapeutic target of hedgehog-driven cancer. FACT inhibitor CBL0137, which has entered human clinical trials against cancer, could effectively suppress multiple mouse and human hedgehog-driven cancer models that are either SMOi-responsive or -resistant both in vitro and in vivo. Mechanistically, CBL0137 exerted its anti-hedgehog activity mainly through targeting the transcription of GLI1/2, which are core transcription factors of hedgehog pathway. ChIP-qPCR analyses further revealed SSRP1 could bind to the promoter regions of GLI1/2, while CBL0137 treatment substantially disrupted these interactions. Moreover, CBL0137 could work synergistically with BET inhibitor or CDK7 inhibitor on antagonizing aberrant hedgehog pathway and growth of either SMOi-responsive or -resistant hedgehog-driven cancer models. Taken together, our study identified FACT inhibition as another promising epigenetic/transcriptional targeted therapeutic strategy for treating hedgehog-driven cancer and overcoming SMOi-resistance.
2021-07-08 | GSE171685 | GEO
Project description:G-quadruplex ligands (G4L) exert their anti-proliferative effect through telomere-dependent and -independent mechanisms, but the inter-relationship between autophagy, cell growth arrest and cell death induced by these ligands remains largely unexplored. 20A is a 2,4,6-triarylpyridine derivative that binds to G4-DNA with fair to excellent selectivity. Here, we demonstrate that this compound impairs cancer cell viability through induction of senescence and apoptotic cell death in a p53-independent manner. In vivo results corroborate those obtained in in vitro, showing that 20A elicits an important tumor growth inhibition in HeLa-xenografted tumor model. The transcriptomic and proteomic analyses reveal the functional enrichment in the growth arrest, DDR and lysosomal pathways upon 20A treatment. More particularly, we find that ATM and autophagy are activated upon 20A treatment. Genetic inhibition of ATM following 20A treatment inhibits both autophagy and senescence and directs cells to apoptosis. Moreover, loss of autophagy by deletion of two essential autophagy genes ATG5 and ATG7 leads to failure of CHK1 activation and increased cell death triggered by 20A. Our results therefore identify ATM as a critical determinant in the balance between senescence and apoptosis and uncover autophagy as one of the key mediators of such regulation. Thus, targeting the ATM/autophagy pathway might be a promising strategy to achieve the maximal therapeutic effect of the 20A G4-ligand.
2019-04-17 | GSE113424 | GEO
Project description:Liver metastases are a leading cause of death among patients with metastatic colorectal cancer. Duration of disease control is short following 2nd-line or later systemic therapy. Liver-directed therapy such as TACE has a higher response rate and improves progression-free survival (PFS), but the benefit is still limited. Cancer cells escape ischemic cell death via autophagy and hypoxia-inducible factor (HIF) activation. We hypothesize that blocking autophagy and the vascular endothelial growth factor (VEGF) pathway will improve both response and PFS following TACE.
| 2376535 | ecrin-mdr-crc
Project description:THZ1 inhibits cancer stemness via Hedgehog pathway.
2021-03-21 | GSE164370 | GEO
Project description:Breast cancer is genetically heterogeneous, and recent studies have underlined a prominent contribution of epigenetics to the development of this disease. To uncover new synthetic lethalities with known breast cancer oncogenes, we screened an epigenome-focused short hairpin RNA library on a panel of engineered breast epithelial cell lines. Here we report a selective interaction between the NOTCH1 signaling pathway and the SUMOylation cascade. Knockdown of the E2-conjugating enzyme UBC9 (UBE2I) as well as inhibition of the E1-activating complex SAE1/UBA2 using ginkgolic acid impairs the growth of NOTCH1-activated breast epithelial cells. We show that upon inhibition of SUMOylation NOTCH1-activated cells proceed slower through the cell cycle and ultimately enter apoptosis. Mechanistically, activation of NOTCH1 signaling depletes the pool of unconjugated small ubiquitin-like modifier 1 (SUMO1) and SUMO2/3 leading to increased sensitivity to perturbation of the SUMOylation cascade. Depletion of unconjugated SUMO correlates with sensitivity to inhibition of SUMOylation also in patient-derived breast cancer cell lines with constitutive NOTCH pathway activation. Our investigation suggests that SUMOylation cascade inhibitors should be further explored as targeted treatment for NOTCH-driven breast cancer. We treated MCF10A and NOTCH1 cells with either DMSO or ginkgolic acid 30 uM for 3 days. Two replicates have been analysed for each condition.
2014-11-21 | E-GEOD-61727 | biostudies-arrayexpress