EGR1 reactivation by histone deacetylase inhibitors promotes synovial sarcoma cell death through the PTEN tumor suppressor

Su, Le; Cheng, Hongwei; Sampaio, Arthur V.; Nielsen, Torsten O.; Underhill, T. Michael

doi:10.1038/onc.2010.204

Cited by 56 publications

(55 citation statements)

References 44 publications

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“…These features are conceivably related to its lower level of HDAC expression and potentially more limited capacity to silence tumor suppressor genes. 28 HDAC1, consistent with published literature, 5 is less expressed than HDAC2 in normal tissues, and HDAC1 protein expression levels among mesenchymal tumors appear to be lower still.…”

Section: Discussionsupporting

confidence: 79%

Histone deacetylase 1 and 2 in mesenchymal tumors

Pacheco

Nielsen

2012

Modern Pathology

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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.

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Section: Discussionsupporting

confidence: 79%

Histone deacetylase 1 and 2 in mesenchymal tumors

Pacheco

Nielsen

2012

Modern Pathology

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“…Induction of EGR1 overexpression by a-bisabolol treatment. It has been reported that EGR1 is a tumor suppressor, because its overexpression markedly inhibits tumor cell growth (31,32) in an Akt-dependent manner.…”

Section: Resultsmentioning

confidence: 99%

“…The suppression of EGR1 enhanced cell survival, consistent with previously published reports. (31,32) Nevertheless, silencing of EGR1 by siRNA did not completely inhibit a-bisabolol-induced apoptosis. Interestingly, a-bisabolol inhibited the growth of MIA Paca2 cells, despite not having any significant effect on EGR1 protein levels in this cell line.…”

Section: Discussionmentioning

confidence: 99%

Antitumor effects of α‐bisabolol against pancreatic cancer

et al. 2011

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In the present study, we investigated whether a-bisabolol, a sesquiterpene alcohol present in essential oils derived from a variety of plants, has antitumor effects against pancreatic cancer. a-Bisabolol induced a decrease in cell proliferation and viability in pancreatic cancer cell lines (KLM1, KP4, Panc1, MIA Paca2), but not in pancreatic epithelial cells (ACBRI515). a-Bisabolol treatment induced apoptosis and suppressed Akt activation in pancreatic cancer cell lines. Furthermore, a-bisabolol treatment induced the overexpression of early growth response-1 (EGR1), whereas EGR1 siRNA decreased the a-bisabolol-induced cell death of KLM1 cells. Tumor growth in both subcutaneous and peritoneal xenograft nude mouse models was significantly inhibited by intragastric administration of 1000 mg ⁄ kg of a-bisabolol, once a week for three weeks. The results indicate that a-bisabolol could be a novel therapeutic option for the treatment of pancreatic cancer. (Cancer Sci 2011; 102: 2199-2205

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“…It has been shown recently that HDAC inhibitorinduced cancer cell apoptosis is initiated primarily in a transcription-dependent manner. 20,21 To explore the underlying mechanisms, we examined the transcription levels of a series of genes involved in the regulation of apoptosis before and after HDAC inhibitor treatment. Among these genes, transcription of Zac1 was markedly increased by TSA (Figure 1a, left and middle panels).…”

Section: Resultsmentioning

confidence: 99%

Zac1 is a histone acetylation-regulated NF-κB suppressor that mediates histone deacetylase inhibitor-induced apoptosis

et al. 2011

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Histone deacetylase (HDAC) inhibitors are a class of promising anticancer reagents. They are able to induce apoptosis in embryonic carcinoma (EC) cells. However, the underlying mechanism remains poorly understood. Here we show that increased expression of zinc-finger protein regulator of apoptosis and cell-cycle arrest (Zac1) is implicated in HDAC inhibitor-induced apoptosis in F9 and P19 EC cells. By chromatin immunoprecipitation analysis we identified that increased Zac1 expression is mediated by histone acetylation of the Zac1 promoter region. Knockdown of Zac1 inhibited HDAC inhibitor-induced cell apoptosis. Moreover, HDAC inhibitors repressed nuclear factor-jB (NF-jB) activity, and this effect is abrogated by Zac1 knockdown. Consistently, Zac1 overexpression suppressed cellular NF-jB activity. Further investigation showed that Zac1 inhibits NF-jB activity by interacting with the C-terminus of the p65 subunit, which suppresses the phosphorylation of p65 at Ser468 and Ser536 residues. These results indicate that Zac1 is a histone acetylation-regulated suppressor of NF-jB, which is induced and implicated in HDAC inhibitor-mediated EC cell apoptosis.

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EGR1 reactivation by histone deacetylase inhibitors promotes synovial sarcoma cell death through the PTEN tumor suppressor

Cited by 56 publications

References 44 publications

Histone deacetylase 1 and 2 in mesenchymal tumors

Histone deacetylase 1 and 2 in mesenchymal tumors

Antitumor effects of α‐bisabolol against pancreatic cancer

Zac1 is a histone acetylation-regulated NF-κB suppressor that mediates histone deacetylase inhibitor-induced apoptosis

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