Characterization of a new small-molecule inhibitor of HDAC6 in glioblastoma
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE143887 | GEO | 2020/01/18
REPOSITORIES: GEO
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Project description:Background: Glioblastoma (GBM) is the most aggressive and lethal brain tumor. Although the histone deacetylase (HDAC)/Sp1 axis promotes growth and temozolomide (TMZ) resistance in glioblastoma, whether HDACs including HDAC6 are involved in modulating long non-coding RNAs (lncRNAs) to affect glioblastoma malignancy remains obscure. Methods: Integrative analysis of microarray and RNA-seq was performed to identify lncRNAs governed by HDAC6. Half-life measurement and RNA-protein pull-down assay combined with iTRAQ-based proteomic analysis were conducted to identify RNA modulators. The effect of LINC00461 on glioblastoma malignancy was evaluated using animal models and cell proliferation-related assays. Functional analysis of the LINC00461 downstream network was performed comprehensively using ingenuity pathway analysis and public databases. Results: We identified a lncRNA, LINC00461, which was substantially increased in TMZ-resistant glioblastoma cells. It was inversely correlated with the survival of mice bearing glioblastoma and was stabilized by interaction between HDAC6 and RNA-binding proteins (RBPs) such as CNOT6 and FUS. Targeting LINC00461 using MPT0B291, an HDAC6 inhibitor, decreased cell division-related proteins via the lncRNA-microRNA (miRNA)-mRNA network and caused cell cycle arrest, thereby suppressing proliferation in parental and TMZ-resistant glioblastoma cells and prolonging the survival of mice bearing glioblastoma. Conclusions: This study sheds light on the role of LINC00461 in glioblastoma malignancy and provides a novel therapeutic strategy for targeting the HDAC6/RBP/LINC00461 axis and its downstream effectors in patients with GBM.
2022-02-08 | GSE182220 | GEO
Project description:ARID1A, encoding a subunit of the SWI/SNF chromatin remodeling complex, is the most mutated epigenetic regulator in human cancers. ARID1A and TP53 mutations are typically mutually exclusive. Therapeutic approaches that correlate with ARID1A mutational status remain a challenge. Here, we show that HDAC6 activity is essential in ARID1A-mutated ovarian cancers. Inhibition of HDAC6 activity using a clinically applicable small molecule inhibitor significantly improved the survival of mice bearing ARID1A-mutated ovarian tumors. This correlated with the suppression of growth and dissemination of ARID1A-mutated, but not wild-type, tumors. The dependence on HDAC6 activity in ARID1A-mutated cells correlated with a direct transcriptional repression of HDAC6 by ARID1A. HDAC6 inhibition selectively promoted apoptosis of ARID1A-mutated cells. HDAC6 directly deacetylated the Lysine 120 residue of p53, a pro-apoptotic post-translational modification. Thus, ARID1A mutation inactivates p53’ apoptotic function by upregulating HDAC6. These results indicate that pharmacological inhibition of HDAC6 is a novel therapeutic strategy involving ARID1A-mutation
2017-07-14 | GSE84405 | GEO
Project description:Despite the anticancer activity of pan-histone deacetylase (HDAC) inhibitors, their clinical use has been limited due to toxicity. However, the development of more specific inhibitors that selectively inhibit individual HDACs is emerging as a novel and well-tolerated alternative. Here, we present the results of the first clinical trial evaluating the activity of ricolinostat (the leading HDAC6 inhibitor) in breast cancer (BC) patients. We have developed a computational network-based algorithm to evaluate the activity of the HDAC6 protein, based on the enrichment of its transcriptional targets in differentially expressed genes (HDAC6 score). Through preclinical in vitro and in vivo studies, we confirmed that the HDAC6 score can stratify the sensitivity of BC cells to ricolinostat treatment and may thus have value as a predictive biomarker. Moreover, analysis of ~3,000 primary human breast cancers showed that ~30% of them present high HDAC6 scores. Based on these results, we designed a phase Ib clinical trial to evaluate the activity of ricolinostat plus nab-paclitaxel in metastatic BC patients. Study results showed that the two agents can be safely combined, that clinical activity is identified specifically in patients with HR+/HER2- disease, and that the HDAC6 score was predictive of response. Expansion of our analysis to other tumor types identified multiple cohorts enriched in high HDAC6 score samples. These results suggest that the HDAC6 score may provide an effective predictive biomarker of ricolinostat sensitivity in multiple human cancers.
2023-02-09 | GSE180606 | GEO
Project description:The gene expression profiles were identified in glioblastoma cells treated with FAK inhibitor Y15, temozolomide alone or with combination of Y15 and Temozolomide DBTRG and U87 were treated with FAK inhibitor Y15 at 10 microM for 24 h; U87 cells were treated with Temozolomide 100 microM for 24 h and Y15+temozolomide at the same dose as each agent alone
2013-01-12 | E-GEOD-43452 | biostudies-arrayexpress
Project description:Despite the anticancer activity of pan-histone deacetylase (HDAC) inhibitors, their clinical use has been limited due to toxicity. However, the development of more specific inhibitors that selectively inhibit individual HDACs is emerging as a novel and well-tolerated alternative. Here, we present the results of the first clinical trial evaluating the activity of ricolinostat (the leading HDAC6 inhibitor) in breast cancer (BC) patients. We have developed a computational network-based algorithm to evaluate the activity of the HDAC6 protein, based on the enrichment of its transcriptional targets in differentially expressed genes (HDAC6 score). Through preclinical in vitro and in vivo studies, we confirmed that the HDAC6 score can stratify the sensitivity of BC cells to ricolinostat treatment and may thus have value as a predictive biomarker. Moreover, analysis of ~3,000 primary human breast cancers showed that ~30% of them present high HDAC6 scores. Based on these results, we designed a phase Ib clinical trial to evaluate the activity of ricolinostat plus nab-paclitaxel in metastatic BC patients. Study results showed that the two agents can be safely combined, that clinical activity is identified specifically in patients with HR+/HER2- disease, and that the HDAC6 score was predictive of response. Expansion of our analysis to other tumor types identified multiple cohorts enriched in high HDAC6 score samples. These results suggest that the HDAC6 score may provide an effective predictive biomarker of ricolinostat sensitivity in multiple human cancers.
2021-04-14 | GSE148623 | GEO
Project description:Characterization of a new small-molecule inhibitor of HDAC6 in glioblastoma
| PRJNA601982 | ENA
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:In the present study, we investigated the importance of histone deacetylase 6 (HDAC6) for glucocorticoid receptor (GR) mediated effects on glucose metabolism, and its potential as a therapeutic target for the prevention of glucocorticoid (GC)-induced diabetes. Dexamethasone (dex)-induced hepatic glucose output and GR translocation were analysed in wildtype (wt) and HDAC6-deficient (HDAC6ko) mice. The effect of the specific HDAC6-inhibitor tubacin was analysed in-vitro. Wt and HDAC6ko mice were subjected to 3 weeks dex treatment before analysis of glucose and insulin tolerance. HDAC6ko mice showed impaired dex-induced hepatic GR translocation. Accordingly, dex induced expression of a large number of hepatic genes was significantly attenuated in mice lacking HDAC6 and by tubacin in-vitro. Glucose output of primary hepatocytes from HDAC6ko mice was diminished. A significant improvement of dex-induced whole-body glucose intolerance as well as insulin resistance in HDAC6ko mice compared to wt littermates was observed. The present study demonstrates that HDAC6 is an essential regulator of hepatic GC stimulated gluconeogenesis and impairment of whole body glucose metabolism through modification of GR nuclear translocation. Selective pharmacological inhibition of HDAC6 may provide a future therapeutic option against the pro-diabetogenic actions of GCs. In this dataset, we include the expression data obtained from isolated RNA of dissected mouse livers using wildtype and HDAC6 deficient animals which were treated over a timespan of 3 weeks with 1mg/kg dexamethasone and vehicle respectively. These data are used to show the hdac6-deficiency mediated attenuation of several dexamethasone induced genes. 12 samples in total were analyzed. 3 samples of different animals of each group (wt vehicle, wt dexamethasone, hdac6ko vehicle and hdac6ko dexamethasone)
2011-12-07 | E-GEOD-34229 | biostudies-arrayexpress
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: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.
2016-12-01 | GSE81710 | GEO