ALKBH5 regulates paclitaxel resistance in NSCLC via inhibiting CEMIP-mediated EMT
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PROVIDER: PRJNA1017379 | ENA |
REPOSITORIES: ENA
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Project description:N6-methyladenosine (m6A) is the most printed and prevalent mRNA modification, which was verified to be closely correlated with cancer occurrence and progression. As m6A demethlyase, the dysregulation of ALKBH5 was observed in various cancer. However, the role and underlying machinery of ALKBH5 in NSCLC pathogenesis, especially the chemo-resistance was poorly elucidated. The current study indicated that ALKBH5 was decreased during paclitaxel (PTX) resistant process and its down-regulation usually implied poor prognosis of NSCLC patients. Over-expression of ALKBH5 in PTX-resistant cells could suppressed cell proliferation and enhanced chemo-sensitivity. Whereas, knockdown of ALKBH5 exerted opposite effect, which further supported the tumor suppressive role of ALKBH5. Over-expression of ALKBH5 also could reverse the EMT process in PTX-resistant cancer cells. Mechanistically, data of RNA-seq, Real-time PCR and western blotting indicted that CEMIP, also known as KIAA1199, may be the downstream target of ALKBH5. And ALKBH5 could negatively regulated the CEMIP level by decreasing its mRNA stability. Collectively, current data demonstrated that ALKBH5/CEMIP axis modulates the EMT process in NSCLC, which in turn regulates chemo-sensitivity of cancer cells to PTX.
2024-03-12 | GSE243199 | GEO
Project description:N6-methyladenosine (m6A) is the most prevalent internal modification of messenger RNA (mRNA) in higher eukaryotes. Here we report ALKBH5 as a new mammalian demethylase that oxidatively removes the m6A modification in mRNA in vitro and inside cells. This demethylation activity of ALKBH5 significantly affects mRNA export and RNA metabolism as well as the assembly of mRNA processing factors in nuclear speckles. Alkbh5-deficient male mice are characterized by impaired fertility resulting from apoptosis that affects meiotic metaphase-stage spermatocytes. In accordance with this defect, we have identified in mouse testes 1552 differentially expressed genes which cover broad functional categories and include spermatogenesis-related mRNAs involved in the p53 functional interaction network. We show that Alkbh5-deficiency impacts the expression levels of some of these mRNAs, supporting the observed phenotype. The discovery of this new RNA demethylase strongly suggests that the reversible m6A modification plays fundamental and broad functions in mammalian cells. RNA-seq in two cell types
2013-02-15 | E-GEOD-40132 | biostudies-arrayexpress
Project description:Non-small cell lung cancer (NSCLC) is a disease with high morbidity and mortality worldwide. NSCLC has significant metastasis ability, which is reported to be promoted by the process of epithelial-mesenchymal transition (EMT). The total flavonoid aglycone extract (TFAE) isolated from Scutellaria baicalensis was reported to inhibit tumor growth and induce cell apoptosis. Here we reconstructed TFAE (reTFAE) according to the main active components and revealed new mechanism in inhibiting EMT process of lung cancer. We provided the solid evidence that the compound mainly composed of baicalein, wogonin, and oroxylin-A presented inhibitory effect on the EMT process of A549 cells, and established the relationship between reTFAE, PI3K/Akt signaling pathways, TWIST1, and glycolysis pathway. The new mechanism we revealed and the new combination of research technologies including bioinformatics technology, chemical biology and molecular biology in our manuscript may be of tremendous interest to a broad range of academic, clinic and industrial researchers.
2022-01-25 | PXD030097 | Pride
Project description:The clinical application of anthracyclines such as doxorubicin (DOX) is limited due to their cardiotoxicity. N6-methyladenosine (m6A) plays an essential role in numerous biological processes. However, the roles of m6A and m6A demethylase ALKBH5 in DOX-induced cardiotoxicity (DIC) remain unclear. In this research, DIC models were constructed using Alkbh5-knockout (KO), Alkbh5-knockin (KI), and Alkbh5-myocardial-specific knockout (ALKBH5flox/flox, αMyHC-Cre) mice. Cardiac function and DOX-mediated signal transduction were investigated. As a result, both Alkbh5 whole-body KO and myocardial-specific KO mice had increased mortality, decreased cardiac function, and aggravated DIC injury with severe myocardial mitochondrial damage. Conversely, ALKBH5 overexpression alleviated DOX-mediated mitochondrial injury, increased survival, and improved myocardial function. Mechanistically, ALKBH5 regulated the expression of Rasal3 in an m6A-dependent manner through posttranscriptional mRNA regulation and reduced Rasal3 mRNA stability, thus activating RAS3, inhibiting apoptosis through the RAS/RAF/ERK signaling pathway, and alleviating DIC injury. These findings indicate the potential therapeutic effect of ALKBH5 on DIC.
2023-03-08 | GSE224215 | GEO
Project description:Inhibiting LCN2 can suppress the development of NSCLC by promoting ferroptosis
| PRJNA998065 | ENA
Project description:Background: N6-methyladenosine (m6A) is the most common and abundant mRNA modification, playing an essential role in biological processes and tumor development. However, the role of m6A methylation in skin cutaneous melanoma (SKCM) is not yet clear. This study analyzed the expression of m6A-related functional genes in SKCM and aimed to explore the key demethylase ALKBH5 mediated m6A modification and its potential mechanism in human SKCM. Methods: Based on public databases, the m6A-related gene expression landscape in SKCM was portrayed. MeRIP-Seq and RNA-Seq were used to recognize the downstream target of ALKBH5. In vivo and in vitro functional phenotype and rescue functional experiments were performed to explore the mechanism of the ALKBH5-ABCA1 axis in SKCM. Results: We found ALKBH5 upregulated in SKCM, associated with poor prognosis. ALKBH5 can promote melanoma cell proliferation, colony formation, migration, and invasion and inhibit autophagy in vitro, facilitating tumor growth and metastasis in vivo. We identified ABCA1, a membrane protein that assists cholesterol efflux, as a downstream target of ALKBH5-mediated m6A demethylation. Finally, our data demonstrated that ALKBH5 promoted SKCM via mediating ABCA1 downregulation by reducing ABCA1 mRNA stability in an m6A-dependent manner. Conclusion: Our findings exhibited the functional value of the key demethylase ALKBH5 mediated m6A modification in the progression of SKCM, suggesting ALKBH5 and its target ABCA1 as potential therapeutic targets in SKCM.
2024-02-29 | GSE253795 | GEO
Project description:Epithelial/mesenchymal transition (EMT) is associated with loss of cell adhesion molecules, such as E-cadherin, and increased invasion, migration, and proliferation in epithelial cancers. In non-small cell lung cancer (NSCLC), EMT is associated with greater resistance to EGFR inhibitors. However, its potential to predict response to other targeted drugs or chemotherapy has not been well characterized. The goal of this study was to develop a robust, platform-independent EMT gene expression signature and to investigate the association of EMT and drug response in NSCLC. A 76-gene EMT signature was derived in 54 DNA-fingerprinted NSCLC cell lines and tested in an independent set of cell lines and in NSCLC patients from the BATTLE clinical trial. The signature classified cell lines as epithelial or mesenchymal independent of the microarray platform and correlated strongly with E-cadherin protein levels, as measured by reverse phase protein array. Higher protein expression of Rab25 (in epithelial lines) and Axl (in mesenchymal lines), two signature genes associated with in EMT in other cancer types, was also confirmed. Mesenchymal cell lines demonstrated significantly greater resistance to EGFR inhibition, independent of EGFR mutation status and were more resistant to drugs targeting the PI3K/Akt pathway. We observed no association between EMT and response to cytotoxic chemotherapies, including cisplatin, pemetrexed, and docetaxel monotherapy and/or doublets (p-values ≥0.2). In NSCLC patients, the EMT signature predicted 8-week disease control in the erlotinib arm, but not in other treatment arms. In conclusion, we have developed a robust EMT signature that predicts resistance to EGFR inhibitors and PI3K/Akt pathway inhibitors. Gene expression profiles were measured in 131 core biopsies from patients with refractory non-small cell lung cancer in the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial. We used the BATTLE dataset to test an EMT gene expression signature trained in cell lines and independant of the microarray platform.
2012-10-25 | E-GEOD-33072 | biostudies-arrayexpress
Project description:HOXD13 Suppresses Prostate Cancer Metastasis and BMP4-induced EMT by Inhibiting SMAD1
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Project description:Time course of TGFbeta induced epithelial mesenchymal transition (EMT) in H358 NSCLC cells.
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