Suppression of CCT3 inhibits tumor growth by downregulating CDK1 expression in melanoma
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ABSTRACT:
PROVIDER: PRJNA604922 | ENA |
REPOSITORIES: ENA
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Project description:The members of the eukaryotic chaperonin family are essential for cell survival. The dysregulation of chaperonin-containing TCP-1 subunit 3 (CCT3) is implicated in the development of several types of malignant tumors. However, its functional role in melanoma remains unknown. Herein, we elucidated the functional contribution of CCT3 to melanoma progression. The results indicated that CCT3 was frequently upregulated in melanoma tissues, and high level of CCT3 is correlated with clinical stage in melanoma patients. Knockdown of CCT3 in melanoma cells markedly inhibited cell proliferation and induced cell apoptosis in vitro and suppressed tumorigenesis in a mouse xenograft model. We also identified the cyclin-dependent kinase 1 (CDK1) as a downstream effector of CCT3 and further evaluation demonstrated that suppression of CCT3 attenuates cell proliferation via downregulating CDK1 expression and CCT3-mediated regulation of cell cycle signaling pathway in melanoma. Collectively, our results provide compelling evidence that CCT3 contributes to melanoma progression via CDK1 and is a potential therapeutic target for melanoma A-375 cells infected with NC lentivirus and CCT3 knockdown lentivirus were prepeared and cultured for RNA extraction and hybridization on Affymetrix microarrays.
2020-02-06 | GSE144788 | GEO
Project description:Activating transcription factor 3 (ATF-3), a cyclic AMP-dependent transcription factor, has been shown to play a regulatory role in melanoma, although its function during tumor progression remains unclear. Here, we demonstrate that ATF-3 exhibits tumor suppressive function in melanoma. Specifically, ATF-3 nuclear expression was significantly diminished with melanoma progression from nevi to primary to metastatic patient melanomas, correlating low expression with poor prognosis. Significantly low expression of ATF-3 was also found in cultured human metastatic melanoma cell lines. Importantly, overexpression of ATF-3 in metastatic melanoma cell lines significantly inhibited cell growth, migration, and invasion in vitro; as well as abrogated tumor growth in a human melanoma xenograft mouse model in vivo. RNA sequencing analysis revealed downregulation of ERK and AKT pathways and upregulation in apoptotic-related genes in ATF-3 overexpressed melanoma cell lines, which was further validated by Western-blot analysis. In summary, this study demonstrated that diminished ATF-3 expression is associated with melanoma virulence and thus provides a potential target for novel therapies and prognostic biomarker applications.
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Project description:Genome integrity requires replication to be completed before chromosome segregation. This coordination essentially relies on replication-dependent activation of a dedicated checkpoint that inhibits CDK1, delaying mitotic onset. Under-replication of Common Fragile Sites (CFSs), however, escapes surveillance, which generates mitotic chromosome breaks. Using human cells, we asked whether this leakage results from insufficient CDK1 inhibition under modest stresses used to destabilize CFSs. We found that tight CDK1 inhibition does suppress CFS instability in so-stressed cells. Molecular combing and Repli-Seq analyses consistently showed a burst of replication initiations in mid S-phase across large origin-poor domains shaped by transcription, including CFSs. CFS rescue and extra-initiations strikingly require availability of essential pre-Replication Complex (pre-RC) proteins during the S-phase, showing that CDK1 inhibition promotes targeted and mistimed pre-RC reloading. In addition to delay mitotic onset, tight checkpoint activation therefore advances replication completion of origin-poor domains at risk of under-replication, two complementary roles preserving genome stability.
2022-12-31 | GSE185282 | GEO
Project description:Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive Schwann cell-derived sarcomas that are sporadic or associated with NF1 gene mutations. Traditional therapies are `usually ineffective for treating MPNSTs, so new targets need to be identified for the treatment of MPNSTs. In the present study, the role of the mitochondrial translocator protein (TSPO) in the regulation of cell proliferation and the cell cycle in MPNSTs was investigated. TSPO expression was lower in MPNSTs than in NFs. Loss-of-function experiments revealed that TSPO deficiency promoted MPNST cell growth, migration, and invasion and influenced the cell cycle in vitro and in vivo. In addition, TSPO depletion suppressed cell apoptosis by downregulating the expression of caspase-3, caspase-8, HSP60, p27, p53, and BCL-2 and suppressed the cell cycle by upregulating CDK1, CDK2, CCNB1 and CCNA2. Furthermore, CDK1 was determined to be an upstream target of TSPO-mediated regulation via RNA-seq, qPCR, and Western blotting. Specifically, depletion of CDK1 weakened the effect of TSPO deficiency on cell proliferation and migration. More importantly, CDK1 knockdown induced significant cell cycle arrest in the G2/M phase. In summary, TSPO deficiency regulates the cell cycle in MPNSTs by targeting CDK1, which may be an effective molecular target for prognosis evaluation and treatment.
2024-06-26 | GSE270880 | GEO
Project description:We addressed the role of cell cycle regulator CDK1 during differentiation by either inhibiting its activity with the specific inhibitor RO3306 (10µM) or by knocking its expression down using specific shRNAs, during mesendoderm differentiation. Human pluripotent stem cells (H9 cells) were synchronized in their cell cycle and then induced to differentiate into mesendoderm for 24h. shRNAs against CDK1 were induced 4 days before starting the differentiation. The CDK1 inhibitor was added to the medium 8h after the induction of differentiation. At the end of the experiment, the cells were harvested and processed for total RNA extraction. RNA-IP was carried out using RiboCluster Profiler RIP-Assay Kit (MBL) following the manufacture’s recommendations.
2021-05-31 | GSE130827 | GEO
Project description:In this study, we found that in ES cells the majority of Cdk1 substrates are localized on chromatin. Cdk1 phosphorylates a large number of proteins involved in epigenetic regulation, including writers and erasers of all major histone marks. High levels of Cdk1 in ES cells phosphorylate and partially inactivate Dot1l, the histone H3 lysine 79 methyltransferase responsible for placing activating H3K79 marks on gene bodies. Decrease of Cdk1 activity during ES cell differentiation de-represses Dot1l, thereby allowing coordinated expression of differentiation genes. These analyses indicate that Cdk1 functions to maintain the epigenetic identity of ES cells.
2020-04-04 | GSE134645 | GEO
Project description:Targeted suppression of ZNF217-induced AKT signaling inhibits tumor growth and metastasis in osteosarcoma
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2023-07-23 | GSE235507 | GEO
Project description:Ailanthone Inhibits Proliferation, Migration and Invasion of Osteosarcoma Cells by Downregulating the Serine Biosynthetic Pathway
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Project description:Biological Relevance and Intent of the Experiment: The objective of this study is to elucidate the role of Cdk1 in cardiac function, specifically its contribution to cardiomyocyte (CM) proliferation and response to injury. Using a heart-specific Cdk1 knockout mouse model, we investigate the molecular and cellular impact of Cdk1 deficiency in the context of myocardial infarction (MI). Cdk1 is known for its regulatory functions in cell cycle progression, and its absence may significantly affect cardiac repair mechanisms post-MI. This research aims to explore whether the lack of Cdk1 impairs CM regeneration or promotes maladaptive remodeling, leading to compromised cardiac function. Overview of the Experimental Workflow: We performed RNA-sequencing (RNA-seq) on heart tissue collected from both wild-type (WT) and cardiac-specific Cdk1 knockout mice subjected to experimental MI. Heart samples were collected 4 days to capture dynamic transcriptional changes associated with Cdk1 loss. Comparative transcriptomic analysis between WT and knockout samples will reveal differentially expressed genes and signaling pathways involved in cardiomyocyte proliferation, apoptosis, and fibrosis. These insights may uncover key pathways driving heart regeneration or degeneration in the absence of Cdk1.
2024-10-31 | E-MTAB-14505 | biostudies-arrayexpress