TTK defines a high-risk Oral Squamous Cell Carcinoma subtype through dual mTORC1/NF-κB activation
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PROVIDER: PRJNA1307438 | ENA |
REPOSITORIES: ENA
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Project description:Oral squamous cell carcinoma (OSCC) remains challenging to treat due to significant tumor heterogeneity, highlighting the need for identifying molecular subtypes with distinct therapeutic vulnerabilities. Here, we present a comprehensive molecular analysis of 709 OSCC cases, integrating single-cell RNA sequencing and bulk transcriptomic data. We identify a distinct molecular subtype of OSCC characterized by co-activation of the mTORC1 and NF-κB pathways, with TTK emerging as a central regulator of this co-activation. This subtype exhibits heightened genomic instability. Using protein mass spectrometry and immunoprecipitation, we demonstrate that TTK activates the NF-κB pathway through interaction with the TAK1-TAB protein complex. Functional in vitro and in vivo experiments further reveal that TTK inhibition significantly enhances cisplatin sensitivity in OSCC. These findings provide a basis for patient stratification and underscore the potential of targeting TTK in therapeutic strategies for this high-risk OSCC subtype.
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Project description:Purpose: Genome-wide DNA-binding analysis for Ttk in intestinal progenitor cells and comparing Su(H) binding sites between seq overexpressed and ttk-RNAi intestinal progenitor cells in Drosophila midgut by DNA adenine methyltransferase identification(DamID) Methods: Dam(Ctrl) , Ttk-Dam transgenes, Su(H)-Dam, Su(H)-Dam&seq and Su(H)-Dam&ttk-RNAi were expressed in intestinal progenitor cells by esg-Gal4.The guts within 2 days was used for DNA adenine methyltransferase identification (DamID), followed by deep sequencing analysis Results: Ttk suppresses neural specific Notch targets through suppressing Seq in intestinal progenitor cells
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Project description:The X-linked deubiquitinase, USP9X, is implicated in multiple cancers by targeting various substrates. Increased expression of USP9X is observed in non-small cell lung cancer (NSCLC) and is correlated with poor prognosis. However, the molecular mechanism for USP9X regulating tumor cell survival and tumorigenesis in NSCLC is less defined. In this study, chemical labeling quantitative proteomic screening was applied to analyze A549 cells with or without USP9X RNA interference, and the resulting data suggested that TTK is a potential substrate of USP9X. Further experimental evidences confirmed that USP9X stabilized TTK via direct interaction and deubiquitination of TTK. Moreover, knockdown of USP9X or TTK inhibited cell proliferation, migration and tumorigenesis, and the immunohistochemical analysis of clinical NSCLC samples showed that the protein expression levels of USP9X and TTK were significantly elevated and positively correlated in tumor tissues. In summary, our data demonstrated that the USP9X-TTK axis may play a critical role in NSCLC, and could be considered as the potential therapeutic target.
2018-05-07 | PXD007726 | Pride
Project description:C-C chemokine ligand 2 (CCL2) plays pivotal roles in tumor formation, progression, and metastasis. Although CCL2 expression has been found to be dependent on the nuclear factor (NF)–κB signaling pathway, the regulation of CCL2 production in tumor cells has remained unclear. We have identified a noncanonical pathway for regulation of CCL2 production that is mediated by mammalian target of rapamycin complex 1 (mTORC1) but independent of NF-κB. Multiple phosphoproteomics approaches identified the transcription factor forkhead box K1 (FOXK1) as a downstream target of mTORC1. Activation of mTORC1 induces dephosphorylation of FOXK1 resulting in transactivation of the CCL2 gene. Inhibition of the mTORC1-FOXK1 axis attenuated insulin-induced CCL2 production as well as the accumulation of tumor-associated monocytes-macrophages and tumor progression in mice. Our results suggest that FOXK1 directly links mTORC1 signaling and CCL2 expression in a manner independent of NF-κB, and that CCL2 produced by this pathway contributes to tumor progression.
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Project description:TTK has been shown to participate in the tumorigenesis of several cancer types but little is known about the function and molecular signalling in ovarian cancer cells. In this study we aim to identify the underlying mechanisms involved in TTK-induced biological functions in the human ovarian cancer cells.
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Project description:Purpose: Next-generation sequencing (NGS) has revolutionized systems-based analysis of cellular pathways. The goals of this study are to compare transcriptome profiling (RNA-seq) of intestinal progenitor cells in Drosophila wild type and ttk-RNAi, dpn overexpressed, Nicd overexpressed and seq&Nicd overexpressed midguts Methods: mRNA profiles of intestinal progenitor cells isolated from 7-day-old wild-type (Ctrl) and ttk-RNAi, dpn overexpressed(dpn OE), Nicd overexpressed(Nicd OE) and seq&Nicd overexpressed(seq&Nicd OE) Drosophila midgut were generated by deep sequencing using Illumina HiSeq 2500. Results: ttk-RNAi in intestinal progenitor cells induces the expression of many neural-specific genes, including dpn and seq. Dpn ectopic expresion explains most of the ttk-RNAi expression profile change. Seq ectopic expression explains the expression of neural-specific Notch targets in the ttk-RNAi intestinal progenitor cells.
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Project description:C-C chemokine ligand 2 (CCL2) plays pivotal roles in tumor formation, progression, and metastasis. Although CCL2 expression has been found to be dependent on the nuclear factor (NF)–κB signaling pathway, the regulation of CCL2 production in tumor cells has remained unclear. We have identified a noncanonical pathway for regulation of CCL2 production that is mediated by mammalian target of rapamycin complex 1 (mTORC1) but independent of NF-κB. Multiple phosphoproteomics approaches identified the transcription factor forkhead box K1 (FOXK1) as a downstream target of mTORC1. Activation of mTORC1 induces dephosphorylation of FOXK1 resulting in transactivation of the CCL2 gene. Inhibition of the mTORC1-FOXK1 axis attenuated insulin-induced CCL2 production as well as the accumulation of tumor-associated monocytes-macrophages and tumor progression in mice. Our results suggest that FOXK1 directly links mTORC1 signaling and CCL2 expression in a manner independent of NF-κB, and that CCL2 produced by this pathway contributes to tumor progression. This SuperSeries is composed of the SubSeries listed below.
2017-11-28 | GSE67922 | GEO
Project description:C-C chemokine ligand 2 (CCL2) plays pivotal roles in tumor formation, progression, and metastasis. Although CCL2 expression has been found to be dependent on the nuclear factor (NF)–κB signaling pathway, the regulation of CCL2 production in tumor cells has remained unclear. Mammalian target of rapamycin complex 1 (mTORC1) is a protein kinase that is activated in various tumor cell types. We have now identified a noncanonical pathway for regulation of CCL2 production that is mediated by mTORC1 but independent of NF-κB. Multiple phosphoproteomics approaches identified the transcription factor forkhead box K1 (FOXK1) as a downstream target of mTORC1, with dephosphorylation of FOXK1 in response to mTORC1 activation resulting in transactivation of the CCL2 gene. Inhibition of the mTORC1-FOXK1 axis attenuated insulin-induced CCL2 production as well as the accumulation of tumor-associated monocytes-macrophages and tumor progression in mice. Our results suggest that FOXK1 directly links mTORC1 signaling and CCL2 expression in a manner independent of NF-κB, and that CCL2 produced by this pathway contributes to tumor progression. Specific inhibition of FOXK1 may thus be a potential therapeutic strategy for cancer.
2017-11-30 | PXD007996 | Pride
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