Selective inhibition of HDAC6 promotes bladder cancer radiosensitization without inducing CXCL1 signalling
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA811513 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18182148_1.fastq.gz | Fastqsanger.gz | |||
| SRR18182148_2.fastq.gz | Fastqsanger.gz | |||
| SRR18182149_1.fastq.gz | Fastqsanger.gz | |||
| SRR18182149_2.fastq.gz | Fastqsanger.gz | |||
| SRR18182150_1.fastq.gz | Fastqsanger.gz |
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Project description:Although bladder-preserving trimodality therapy is recognized for patients with muscle-invasive bladder cancer (MIBC), chemotherapy can have toxic effects. Inhibitors to histone deacetylases (HDACis) have been identified as an effective strategy to enhance the radiotherapy (RT) effect, and several of them have clinical efficacy in BC. However, little is known about how a specific HDAC6 inhibitor (HDAC6i) acts in concert with RT. Knockdown of HDAC6 enhanced the radiosensitization of BC cells and increased γH2AX accumulation, similar to the effect of panobinostat, a pan-HDACi. Applying tubacin, a selective HDAC6i, to T24 cells induced H3K9ac and α-tubulin acetylation, and significantly decreased clonogenic cell survival when combined with RT. Further transcriptomic analysis of shHDAC6-transduced T24 cells under irradiation showed that genes that were highly downregulated compared to the levels in response to RT alone were significantly enriched in the inflammatory response. Moreover, HDAC6 knockdown counteracted the RT-induced mRNA expression of CXCL1, SERPINE1, SDC1 and SDC2. Importantly, tubacin suppressed RT-promoted invaded/migrated T24 cells, whereas panobinostat elevated RT-induced CXCL1 expression and invasion/migration abilities. This phenotype was significantly abrogated by the CXCL1 antibody, indicating that RT-induced CXCL1 is the key regulator contributing to BC malignancy. Immunohistochemical evaluation of tumours from BC patients supported the correlation between CXCL1 overexpression and poor prognosis. Unlike the pan-HDACi, the selective HDAC6i tubacin can enhance BC radiosensitization and suppress RT-induced oncogenic CXCL1-Snail signalling, thus further advancing the therapeutic potential of tubacin with RT.
2023-04-07 | GSE197659 | GEO
Project description:BackgroundAlthough trimodality therapy resecting tumours followed by chemoradiotherapy is emerged for muscle-invasive bladder cancer (MIBC), chemotherapy produces toxicities. Histone deacetylase inhibitors have been identified as an effective strategy to enhance cancer radiotherapy (RT).MethodsWe examined the role of HDAC6 and specific inhibition of HDAC6 on BC radiosensitivity by performing transcriptomic analysis and mechanism study.ResultsHDAC6 knockdown or HDAC6 inhibitor (HDAC6i) tubacin exerted a radiosensitizing effect, including decreased clonogenic survival, increased H3K9ac and α-tubulin acetylation, and accumulated γH2AX, which are similar to the effect of panobinostat, a pan-HDACi, on irradiated BC cells. Transcriptomics of shHDAC6-transduced T24 under irradiation showed that shHDAC6 counteracted RT-induced mRNA expression of CXCL1, SERPINE1, SDC1 and SDC2, which are linked to cell migration, angiogenesis and metastasis. Moreover, tubacin significantly suppressed RT-induced CXCL1 and radiation-enhanced invasion/migration, whereas panobinostat elevated RT-induced CXCL1 expression and invasion/migration abilities. This phenotype was significantly abrogated by anti-CXCL1 antibody, indicating the key regulator of CXCL1 contributing to BC malignancy. Immunohistochemical evaluation of tumours from urothelial carcinoma patients supported the correlation between high CXCL1 expression and reduced survival.ConclusionUnlike pan-HDACi, the selective HDAC6i can enhance BC radiosensitization and effectively inhibit RT-induced oncogenic CXCL1-Snail-signalling, thus further advancing its therapeutic potential with RT.
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Project description:Histone deacetylase 6 (HDAC6) is overexpressed in multiple myeloma (MM) patients and may be involved in the acquisition of resistance to conventional treatments. Here, we propose a two-residue mutation impairing the HDAC6 ZnF-UBP domain. HDAC6 knockout and ZnF-UBP mutant RPMI 8226 MM cell lines were generated using CRISPR-Cas9. MM cells harboring this mutation showed impaired aggresome formation, cell growth and a dysregulated gene expression profile in a more pronounced manner than the HDAC6 knockout cells.
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Project description:The Tip60 (also known as Kat5) lysine acetyltransferase functions broadly as a transcriptional co-activator that acetylates histones. In contrast, Tip60 functions in embryonic stem cells (ESCs) both to silence genes that promote differentiation and to activate genes required for proliferation. The mechanism by which Tip60 functions as a repressor is unknown. Here we show that the class II histone deacetylase Hdac6 co-purifies with Tip60-p400 complex from ESCs and is necessary for complete silencing of most differentiation genes targeted by Tip60. In contrast to differentiated cells, where Hdac6 is mainly cytoplasmic and does not interact with Tip60, Hdac6 is largely nuclear in ESCs and neural stem cells (NSCs) and interacts with Tip60-p400 in both cell types. Hdac6 is enriched at promoters bound by Tip60-p400 in ESCs, but while Tip60 binds on both sides of transcription start sites (TSSs), Hdac6 binding overlaps with only the downstream Tip60 peak. Surprisingly, Hdac6 does not deacetylate histones at these sites, but rather is required for Tip60 binding. These data suggest that nuclear exclusion of Hdac6 during differentiation plays a major role in modulation of Tip60-p400 function. We determined the genome-wide localization of Tip60 and Hdac6 in mouse ES cells, and examined genomic binding profiles of Tip60 and Hdac6 upon indicated knockdown by ChIP-seq. We examined genomic binding profiles of p400 upon indicated knockdown by ChIP-seq.
2013-11-20 | E-GEOD-42209 | biostudies-arrayexpress
Project description:Histone deacetylases (HDACs) are crucial regulators of gene expression, DNA synthesis, and cellular processes, making them essential targets in cancer research. HDAC6, specifically, influences protein stability and chromatin dynamics. Despite HDAC6's potential therapeutic value, its exact role in gene regulation and chromatin remodeling needs further clarification. This study examines how HDAC6 inactivation influences lysine acetyltransferase P300 stabilization and subsequent effects on chromatin structure and function in cancer cells. We employed the HDAC6 inhibitor ITF3756, siRNA, or CRISPR/Cas9 gene editing to inactivate HDAC6 in different epigenomic backgrounds. Constantly, this inactivation led to significant changes in chromatin accessibility, particularly increased acetylation of histone H3 lysines 9, 14, and 27 (ATAC-seq and H3K27Ac ChIP-seq analysis). Transcriptomics, proteomics, and gene ontology analysis revealed gene changes in cell proliferation, adhesion, migration, and apoptosis. Significantly, HDAC6 inactivation altered P300 ubiquitination, stabilizing P300 and leading to downregulating genes critical for cancer cell survival. Our study highlights the substantial impact of HDAC6 inactivation on the chromatin landscape of cancer cells and suggests a role for P300 in contributing to the anticancer effects. The stabilization of P300 with HDAC6 inhibition proposes a potential shift in therapeutic focus from HDAC6 itself to its interaction with P300. This finding opens new avenues for developing targeted cancer therapies, improving our understanding of epigenetic mechanisms in cancer cells.
2024-08-19 | GSE273645 | GEO
Project description:Histone deacetylases (HDACs) are crucial regulators of gene expression, DNA synthesis, and cellular processes, making them essential targets in cancer research. HDAC6, specifically, influences protein stability and chromatin dynamics. Despite HDAC6's potential therapeutic value, its exact role in gene regulation and chromatin remodeling needs further clarification. This study examines how HDAC6 inactivation influences lysine acetyltransferase P300 stabilization and subsequent effects on chromatin structure and function in cancer cells. We employed the HDAC6 inhibitor ITF3756, siRNA, or CRISPR/Cas9 gene editing to inactivate HDAC6 in different epigenomic backgrounds. Constantly, this inactivation led to significant changes in chromatin accessibility, particularly increased acetylation of histone H3 lysines 9, 14, and 27 (ATAC-seq and H3K27Ac ChIP-seq analysis). Transcriptomics, proteomics, and gene ontology analysis revealed gene changes in cell proliferation, adhesion, migration, and apoptosis. Significantly, HDAC6 inactivation altered P300 ubiquitination, stabilizing P300 and leading to downregulating genes critical for cancer cell survival. Our study highlights the substantial impact of HDAC6 inactivation on the chromatin landscape of cancer cells and suggests a role for P300 in contributing to the anticancer effects. The stabilization of P300 with HDAC6 inhibition proposes a potential shift in therapeutic focus from HDAC6 itself to its interaction with P300. This finding opens new avenues for developing targeted cancer therapies, improving our understanding of epigenetic mechanisms in cancer cells.
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Project description:Foxp3+ T-regulatory cells (Tregs) are key to immune homeostasis such that their diminished numbers or function can cause autoimmunity and allograft rejection. Foxp3+ Tregs express histone/protein deacetylases (HDACs) that regulate chromatin remodeling, gene expression and protein function. Pan-HDAC inhibitors developed for oncology enhance Treg production and suppression but have limited non-oncologic applications given their broad effects. We show, using HDAC6-deficient mice and WT mice treated with HDAC6-specific inhibitors, that HDAC6 inhibition promotes Treg suppressive activity in models of inflammation and autoimmunity, including multiple forms of experimental colitis and fully MHC-incompatible cardiac allograft rejection. Many of the beneficial effects of HDAC6 targeting are also achieved by inhibition of the HDAC6-regulated protein, HSP90. Hence, selective targeting of a single HDAC isoform, HDAC6, or its downstream target, HSP90, can promote Treg-dependent suppression of autoimmunity and transplant rejection. RNA from three independent samples from magnetically separated CD4+CD25+ Treg of HDAC6 knock out, compared to wild type (C57BL6) control
2011-05-01 | E-GEOD-27896 | biostudies-arrayexpress
Project description:Analysis of mouse ESCs overexpressing HDAC6. Histone deacetylase 6 (Hdac6) was discovered as a deacetylase of α-tubulin and functions in cell migration, immunity and resistance to virus infection in vitro. HDAC6 overexpression ESCs and control ESCs were selected for RNA extraction and hybridization on Agilent microarrays. Results provide insight into the role of HDAC6 in the mouse ESCs.
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