Dataset Information

ACAT1 promotes bladder tumorigenesis by inducing cell cycle via AKT/GSK3β/c-Myc signaling pathway

ABSTRACT: Acetyl-CoA acetyltransferase 1 (ACAT1) played a key role in regulating gene expression and tumorigenesis. Nevertheless, the biological function of ACAT1 in bladder cancer (BLCA) has yet to be elucidated. This study aimed to elucidate the bioinformatics features and biological functions of ACAT1 in BLCA. Here, we demonstrate for the first time that ACAT1 is elevated in BLCA tissues, correlating with specific clinicopathological features and an unfavorable prognosis for survival in BLCA patients. ACAT1 emerged as an independent risk factor in BLCA. Phenotypically, ACAT1 knockdown inhibited the proliferation and migration of BLCA cells both in vivo and in vitro, whereas ACAT1 overexpression yielded the opposite phenotype. Mechanistically, ACAT1 enhances BLCA cells proliferation by activating cell cycle through AKT/GSK3β/c-Myc signaling pathway. In conclusion, this study identifies ACAT1 as an oncogene in BLCA, demonstrating its capability to promote proliferation and metastasis of BLCA. This suggests that ACAT1 may serve as a potential molecular target for the diagnosis and treatment of BLCA.

ORGANISM(S): Homo sapiens

PROVIDER: GSE248825 | GEO | 2024/06/12

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Background: The histone-lysine N-methyltransferase SMYD1, which is specific to striated muscle, plays a crucial role in regulating early heart development. Its deficiency has been linked to the occurrence of congenital heart disease. Nevertheless, the precise mechanism by which SMYD1 deficiency contributes to congenital heart disease remains unclear. Methods: We established a SMYD1 knockout pluripotent stem cell line and a doxycyclineinducible SMYD1 expression pluripotent stem cell line to investigate the functions of SMYD1 utilizing an in vitro-directed myocardial differentiation model. Results: Cardiomyocytes lacking SMYD1 displayed drastically diminished differentiation efficiency, concomitant with heightened proliferation of cardiac progenitor cells during the early cardiac differentiation stage. These cellular phenotypes were confirmed through experiments inducing the re-expression of SMYD1. Transcriptome sequencing and small molecule inhibitor intervention suggested that the GSK3β/β-catenin/ERK signaling pathway was involved in the proliferation of cardiac progenitor cells. Chromatin immunoprecipitation demonstrated that SMYD1 acted as a transcriptional activator of GSK3β through histone H3 Lysine 4 trimethylation. Additionally, dualluciferase analyses indicated that SMYD1 could interact with the promoter region of GSK3β, thereby augmenting its transcriptional activity. Moreover, administering insulin and Insulin-like growth factor 1 can enhance the efficacy of myocardial differentiation in SMYD1 knockout cells. Conclusions: Our research indicated that the participation of SMYD1 in the GSK3β/β-catenin/ERK signaling cascade modulated the proliferation of cardiac progenitor cells during myocardial differentiation. This process was partly reliant on the transcription of GSK3β. Our research provided a novel insight into the genetic modification effect of SMYD1 during early myocardial differentiation. The findings were essential to the molecular mechanism and potential interventions for congenital heart disease.

Project description:Exploiting an Asp-Glu “switch” in glycogen synthase kinase 3 to design paralog selective inhibitors for use in acute myeloid leukemia: Genome-wide transcriptional profile for the GSK3β selective inhibitor BRD3731. Glycogen synthase kinase 3 (GSK3), a key regulatory kinase in the WNT pathway, remains a therapeutic target of interest in many diseases. While dual GSK3α/β inhibitors have entered clinical trials, none has successfully translated to clinical application. Mechanism-based toxicities, driven in part by the inhibition of both GSK3 paralogs and subsequent β-catenin stabilization, are a concern in the translation of this target class to cancer therapy, particularly for the treatment of acute myeloid leukemia (AML). Knockdown of GSK3α or GSK3β individually does not increase β-catenin in certain cellular subtypes and offers a conceptual resolution to targeting GSK3: paralog-selective inhibition. However, only inadequate chemical tools exist. The design of selective ATP competitive inhibitors poses a drug discovery challenge due to the high homology (95% identity, 100% similarity) in their ATP binding domains. Taking advantage of an Asp133®Glu196 “switch” in their hinge binding domains, we present a rational design strategy towards the discovery of a paralog selective set of GSK3 inhibitors. These first-in-class GSK3α and GSK3β selective inhibitors provided insights into GSK3 targeting in AML where GSK3α has been identified as a therapeutic target using genetic approaches. Our GSK3α selective compound (BRD0705) inhibits kinase function and does not stabilize β-catenin, mitigating potential neoplastic concerns. BRD0705 induces myeloid differentiation and impairs colony formation in AML cells while no effect is observed on normal hematopoietic cells. Moreover, BRD0705 impairs leukemia initiation and prolongs survival in AML mouse models. These studies validate feasibility of paralog selective GSK3α inhibition offering a promising therapeutic approach in AML.

Project description:Similar to resting mature B cells, where the B-cell antigen receptor (BCR) is essential for cellular survival, surface BCR expression is conserved in most mature B cell lymphomas. The identification of activating BCR mutations and the growth disadvantage upon BCR knockdown of cells of certain lymphoma entities has led to the view that BCR signaling is required for tumour cell survival. Consequently, the BCR signaling machinery has become a new target in the therapy of B cell malignancies. Here, we studied the effects of BCR ablation on MYC-driven mouse B cell lymphomas and compared them to observations in human Burkitt lymphoma. Whereas BCR ablation did not, per se, significantly affect lymphoma growth, BCR-negative (BCR-) tumour cells rapidly disappeared in the presence of their BCR-expressing (BCR+) counterparts in vitro and in vivo. This required neither cellular contact, nor factors released by BCR+ tumour cells. Instead, BCR loss induced the rewiring of central carbon metabolism increasing the sensitivity of receptor-less lymphoma cells to nutrient restriction. The BCR attenuated GSK3β activity to support MYC-controlled gene expression. BCR- tumour cells exhibited increased GSK3β activity and were rescued from their competitive growth disadvantage by GSK3β. BCR-negative lymphoma variants that restored competitive fitness, normalized GSK3β following constitutive activation of the MAPK pathway, commonly through Ras mutations. Similarly, in Burkitt lymphoma, activating RAS mutations may propagate Ig-crippled tumour cells, which usually represent a minority of the tumour bulk. Thus, while BCR expression enhances lymphoma cell fitness, BCR-targeted therapies may profit from combinations with drugs targeting BCR-less tumour cells. In this dataset, we included the expression data obtained from BCR-positive (BCR+) and BCR-negative (BCR-) lymphoma cells co-cultured for 4 days in presence or absence of GSK3b inhibitor, CHIR99021. These data were used to obtain genes that are regulated by the BCR through GSK3b inhibition.

Dataset Information

ACAT1 promotes bladder tumorigenesis by inducing cell cycle via AKT/GSK3β/c-Myc signaling pathway

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets