CHI-KAT8i5 suppresses ESCC tumor growth through inhibiting KAT8 mediate c-Myc stability
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ABSTRACT:
PROVIDER: PRJNA1189422 | ENA |
REPOSITORIES: ENA
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Project description:The integrated analysis of histone modifier enzymes in solid tumor, especially in esophageal squamous cell carcinoma (ESCC) is still inadequate. Here, we investigate the expression levels of histone modifier enzymes in ESCC tissues. Notably, KAT8 is identified as a prognostic and therapeutic biomarker in ESCC. Esophageal tissue-specific deletion of KAT8 mice exhibite less tumor burden after induction of tumorigenesis via 4NQO treatment compared with wild-type mice. Meanwhile, silencing KAT8 significantly suppresses tumor growth in CDX and PDX model. Mechanically, we confirm that KAT8 regulates c-Myc protein stability by directly binding it. Furthermore, we design and screen a specific KAT8 inhibitor (CHI-KAT8i5) that significantly attenuate tumor growth in vitro and in vivo, providing promising potential for clinical application. Thus, our work identify KAT8 could serve as a potential clinically relevant biomarker and therapeutic target in patients with ESCC disease and optimize KAT8 inhibitor is a promising lead candidate for ESCC therapy.
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Project description:Purpose: The goal of this study is to compare oocyte transcriptome profiling in WT and Kat8 Gdf9 cKO mice Methods: Oocyte mRNA profiles of 2 weeks old WT and Kat8 Gdf9 cKO mice were generated by deep sequencing using Illumina HiSeq 2500. Results: Using an optimized data analysis workflow, we mapped about 54-63 million sequence reads per sample to the mouse genome (build mm10) and identified 18,468 transcripts in the oocytes of WT and Kat8 Gdf9 cKO mice. Approximately 5% of the transcripts showed differential expression between the WT and Kat8 Gdf9 cKO oocyte, with a fold change ≥1.5 and p value <0.05. Conclusions: Our study represents the first detailed analysis of oocyte transcriptomes after kat8 deletion, which is generated by RNA-seq technology.Our results show that Kat8 affects numerous gene expression in mouse oocytes.
2017-03-25 | GSE97026 | GEO
Project description:Dysregulation of MOF (MYST1, KAT8), a highly conserved H4K16 acetyltransferase, plays important roles in human cancers. However, its expression and function in esophageal squamous cell carcinoma (ESCC) remain unknown. Here, we report that MOF is highly expressed in ESCC tumors and predicts a worse prognosis. Depletion of MOF in ESCC significantly impedes tumor growth and metastasis both in vitro and in vivo, whereas ectopic expression of MOF but not enzyme inactive mutant (MOF E350Q) promotes ESCC progression, suggesting that MOF acetyltransferase activity is crucial for its oncogenic activity. Further analysis reveals that USP10, a deubiquitinase highly expressed in ESCC, binds to and protects MOF from proteosome-dependent protein degradation. MOF stabilization by USP10 promotes H4K16ac enrichment in the ANXA2 promoter to stimulate ANXA2 transcription, which subsequently activates Wnt/ β-Catenin signaling to facilitate ESCC progression. Our findings highlight a novel USP10/MOF/ANXA2 axis as a promising therapeutic target for ESCC.
2024-01-09 | GSE241066 | GEO
Project description:KAT8 is a lysine acetyltransferase and is involved in multiple important biological processes including cancer. The well-known function of KAT8 is catalyzing acetylation on histone H4, which regulates gene expression and chromatin decompaction. Besides catalytic HAT domain, the function of Tudor-knot domain of KAT8 remains largely unclear. Here, we report a novel function of Tudor-knot domain in facilitates histone acetyltransferase activity on H4K16ac. One hot-spot cancer mutation on Tudor-knot domain of KAT8 inhibits its interaction with nucleosome and reduces H4K16ac level both in vitro and in cells without altering the chromatin occupancy. Interestingly, this Tudor-knot mutation does not influence acetylation activity of KAT8 on p53, a non-histone substrate, suggests the important function of KAT8 Tudor-knot domain in the substrate specific catalytic regulation.
2023-12-24 | GSE245008 | GEO
Project description:KAT8 is a lysine acetyltransferase and is involved in multiple important biological processes including cancer. The well-known function of KAT8 is catalyzing acetylation on histone H4, which regulates gene expression and chromatin decompaction. Besides catalytic HAT domain, the function of Tudor-knot domain of KAT8 remains largely unclear. Here, we report a novel function of Tudor-knot domain in facilitates histone acetyltransferase activity on H4K16ac. One hot-spot cancer mutation on Tudor-knot domain of KAT8 inhibits its interaction with nucleosome and reduces H4K16ac level both in vitro and in cells without altering the chromatin occupancy. Interestingly, this Tudor-knot mutation does not influence acetylation activity of KAT8 on p53, a non-histone substrate, suggests the important function of KAT8 Tudor-knot domain in the substrate specific catalytic regulation.
2023-12-24 | GSE245007 | GEO
Project description:To understand the difference of protein expression between paired esophageal squamous cell carcinoma (ESCC) and adjacent normal tissues, we collected 10 paired ESCC and normal tissues from surgical resected specimems for high-throughput proteomic experiments. From comparative analysis, the dysregulated signaling pathways in ESCC could be uncovered.
2020-08-11 | PXD019834 | Pride
Project description:To discover ESCC related proteins, we used SWATH to quantify the protein abundance between ESCC and adjacent tissues. Briefly, we pooled 10 ESCCtissues and their corresponding adjacent tissues for SWATH acquisition with three replicates.Three DDA repeats were also acquired with the pooled 10-paired ESCC tissue.The trypsin digested peptide mixture was analyzed by AB SCIEX 5600 (AB SCIEX).The database searching procedure was achieved using ProteinPilot v4.5 (AB Sciex). The database is IPI_homo_sapiens_V3.87.
2015-09-22 | PXD001764 | Pride
Project description:Histone acetylation is associated with open chromatin and transcriptionally active genes. Specifically, acetylation of lysine 16 on histone H4 (H4K16ac) has been shown to prevent the assembly of nucleosomal arrays in vitro. This modification is catalyzed by the MYST-family histone acetyltransferase KAT8 (also known as MOF and MYST1), which is part of two distinct chromatin-associated complexes: NSL and MSL. While extensively studied in Drosophila, the functions of H4K16ac and the two KAT8-containing complexes in mammalian cells are not well understood. Here, we demonstrate a surprising complex-dependent activity of KAT8. We found that KAT8 catalyzes H4K5 and H4K8 acetylation as part of the NSL complex, whereas it catalyzes the bulk of H4K16 acetylation as part of the MSL complex. Furthermore, we show that the core proteins of the MSL complex and H4K16ac are not required for cell proliferation and global chromatin accessibility, whereas the NSL complex is essential for cell survival, as it is enriched at the promoters of housekeeping genes and is required for their transcription initiation. In summary, we show that KAT8 switches catalytic activity and function depending on its associated proteins, and that, as part of the NSL complex, it catalyzes H4K5 and H4K8 acetylation required for the expression of genes essential for cell survival.
2021-02-28 | GSE158521 | GEO
Project description:Histone acetylation is associated with open chromatin and transcriptionally active genes. Specifically, acetylation of lysine 16 on histone H4 (H4K16ac) has been shown to prevent the assembly of nucleosomal arrays in vitro. This modification is catalyzed by the MYST-family histone acetyltransferase KAT8 (also known as MOF and MYST1), which is part of two distinct chromatin-associated complexes: NSL and MSL. While extensively studied in Drosophila, the functions of H4K16ac and the two KAT8-containing complexes in mammalian cells are not well understood. Here, we demonstrate a surprising complex-dependent activity of KAT8. We found that KAT8 catalyzes H4K5 and H4K8 acetylation as part of the NSL complex, whereas it catalyzes the bulk of H4K16 acetylation as part of the MSL complex. Furthermore, we show that the core proteins of the MSL complex and H4K16ac are not required for cell proliferation and global chromatin accessibility, whereas the NSL complex is essential for cell survival, as it is enriched at the promoters of housekeeping genes and is required for their transcription initiation. In summary, we show that KAT8 switches catalytic activity and function depending on its associated proteins, and that, as part of the NSL complex, it catalyzes H4K5 and H4K8 acetylation required for the expression of genes essential for cell survival.
2021-02-28 | GSE158736 | GEO