Histone deacetylase inhibitors induce cell death and enhance the apoptosis-inducing activity of TRAIL in Ewing’s sarcoma cells

Sonnemann, Jürgen; Dreyer, Linn; Hartwig, Maite; Palani, Chithra D.; Hong, Le Van; Klier, Ulrike; Bröker, Barbara M.; Völker, Uwe; Beck, James F.

doi:10.1007/s00432-007-0227-8

Cited by 76 publications

(72 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…13 Several HDAC inhibitors have been shown to be effective in Ewing preclinical models, [14][15][16] and comparable findings have now been reported in other translocation-associated sarcomas, including synovial sarcoma, 17 clear cell sarcoma, myxoid liposarcoma and desmoplastic small-blue round-cell tumor. 18 Despite this body of preclinical evidence supporting HDAC inhibitors as therapeutic agents in translocation-associated sarcomas, the well-documented involvement of class I HDACs in cancer biology, 19 and the recent opening of phase II clinical trials testing these agents in sarcomas, little information exists on the expression of the enzymes targeted by these drugs in mesenchymal neoplasms.…”

mentioning

confidence: 71%

Histone deacetylase 1 and 2 in mesenchymal tumors

Pacheco

Nielsen

2012

Modern Pathology

View full text Add to dashboard Cite

Histone deacetylases (HDACs) have a critical role in epigenetic gene silencing, rendering a compact chromatin structure by removing acetyl groups from lysine residues within the tails of core histones, thereby repressing gene expression. Epigenetic transcriptional dysregulation is an important oncogenic mechanism in some sarcomas associated with translocations, for which antitumor activity by HDAC inhibitors has been shown in preclinical studies. Nevertheless, the expression of the protein targets of these drugs has not yet been broadly surveyed in this neoplasia. In this study, we assess the expression of HDAC1 and 2 by immunohistochemistry in a tissue microarray series of 1332 cases, representing 44 categories of malignant and borderline mesenchymal tumors. HDAC2 was the more highly expressed isoform, and was more strongly expressed in translocation-associated sarcomas than in other mesenchymal tumors or normal tissues. HDAC1, in contrast, displayed lower expression in translocation-associated sarcomas than in other mesenchymal tumors or in normal tissues. These results indicate that HDAC1 and HDAC2 are differentially expressed in mesenchymal neoplasms, and suggest that HDAC2 is the isoform more likely contributing to the pathogenesis of many translocation-associated sarcomas and to their response to HDAC inhibitors.

show abstract

mentioning

confidence: 71%

Histone deacetylase 1 and 2 in mesenchymal tumors

Pacheco

Nielsen

2012

Modern Pathology

View full text Add to dashboard Cite

show abstract

“…The connection between HDAC activity and Ewing sarcoma has been noted previously. Romedepsin had been shown to decrease EWSR1-FLI1 mRNA levels (41), and Romedepsin, Vorinostat, and Entinostat exhibited anti-proliferative activity on Ewing cells (41,42). In addition, Vorinostat treatment reversed the EWSR1-FLI1-mediated transcriptional repressive signature in Ewing sarcoma cells (43).…”

Section: Discussionmentioning

confidence: 99%

High-throughput small molecule screen identifies inhibitors of aberrant chromatin accessibility

Pattenden

Simon

Wali

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Mutations in chromatin-modifying proteins and transcription factors are commonly associated with a wide variety of cancers. Through gain-or loss-of-function, these mutations may result in characteristic alterations of accessible chromatin, indicative of shifts in the landscape of regulatory elements genome-wide. The identification of compounds that reverse a specific chromatin signature could lead to chemical probes or potential therapies. To explore whether chromatin accessibility could serve as a platform for small molecule screening, we adapted formaldehyde-assisted isolation of regulatory elements (FAIRE), a chemical method to enrich for nucleosomedepleted genomic regions, as a high-throughput, automated assay. After demonstrating the validity and robustness of this approach, we applied this method to screen an epigenetically targeted small molecule library by evaluating regions of aberrant nucleosome depletion mediated by EWSR1-FLI1, the chimeric transcription factor critical for the bone and soft tissue tumor Ewing sarcoma. As a class, histone deacetylase inhibitors were greatly overrepresented among active compounds. These compounds resulted in diminished accessibility at targeted sites by disrupting transcription of EWSR1-FLI1. Capitalizing on precise differences in chromatin accessibility for drug discovery efforts offers significant advantages because it does not depend on the a priori selection of a single molecular target and may detect novel biologically relevant pathways.chromatin | Ewing sarcoma | high throughput screening | FAIRE | histone deacetylase inhibitor A growing range of human cancers have been associated with mutations in genes encoding proteins that regulate chromatin, the assembly of proteins and DNA that control DNAtemplated processes, including transcription and replication (1, 2). Small molecule drugs and chemical probes offer an approach to explore the biological consequences of these mutations and are emerging as a therapeutic strategy to target disease pathways. Drugs targeting histone deacetylase (HDAC) enzymes, the bromodomain reader BRD4, and DNA methylation have already received regulatory approval or have entered clinical testing, and chemical probes have been developed against a broad range of chromatin regulators, such as the methyltransferases (3) DOT1L (4), EZH2 (5-8), and G9a (9, 10), and the reader proteins L3MBTL3 (11) and BRD4 (12-14). However, transcription factors that lack enzymatic activity or binding pockets with targetable molecular features have been considered "undruggable," and a reductionist approach based on identification of their molecular targets has largely failed.The majority of Ewing sarcomas, highly malignant pediatric bone and soft tissue tumors, harbor a chromosomal translocation that joins the amino-terminal domain of EWSR1 with the DNA binding domain of the ETS transcription factor family member FLI1 to generate the chimeric transcription factor EWSR1-FLI1 (15). Translocations with other ETS genes are detected in most of the remaining tumors, y...

show abstract

“…Acetylation neutralizes the positive charges on the core histone, and converts the chromatin to a more open state, enhancing the access of the transcriptional machinery, including RNA polymerase II, to the promoter region for gene expression. HDACis have been used as anti-cancer drugs, because they activate the expression of the TRAIL, Fas, Bid, and p53 genes to induce growth arrest and/or apoptosis of cancer cells (Bandyopadhyay et al, 2004;Nakata et al, 2004;Ogawa et al, 2004;Ruefli et al, 2001;Sonnemann et al, 2007) by inhibiting HDAC activities, and they also have anti-angiogenic and anti-metastatic effects (Bolden et al, 2006). In addition, HDACi can enhance anti-tumor immunity, either by directly affecting malignant cells to make them more attractive immune targets, or by altering immune cell activity and/or cytokine production.…”

Section: Tsa-induced Transgene Activationmentioning

confidence: 99%