Histone Deacetylase Inhibitor FK228 Activates Tumor Suppressor <i>Prdx1</i> with Apoptosis Induction in Esophageal Cancer Cells

Hoshino, Isamu; Matsubara, Hisahiro; Hanari, Naoyuki; Mori, Mikito; Nishimori, Takanori; Yoneyama, Yoshio; Akutsu, Yasunori; Sakata, Haruhito; Matsushita, Hiroshi; Seki, Naohiko; Ochiai, Takenori

doi:10.1158/1078-0432.ccr-05-0840

Cited by 56 publications

(47 citation statements)

References 38 publications

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“…Moreover, the Prdx1 knockout mice generated malignancies in the intestine, lymphomas, and sarcomas with a high frequency (6). In addition, we previously reported that FK228, one of the novel HDAC inhibitors, induced growth inhibition and apoptosis in ESCC (7). HDAC plays a fundamental role in regulating gene expression and chromatin assembly (9,10).…”

Section: Discussionmentioning

confidence: 99%

“…Neumann et al (6) showed, using Prdx1 knockout mice, that Prdx1 expression correlated with the reactive oxygen species and the incidence of malignant disease. Moreover, our previous study using a cDNA microarray showed that one of the novel histone deacetylase (HDAC) inhibitors, FK228, induced the Prdx1 expression in the esophageal cancer cell lines and that the expression was associated with the cell toxicity of FK228 (7). The deregulation of HDACs can cause malignant diseases.…”

Section: Introductionmentioning

confidence: 99%

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Tumor suppressor Prdx1 is a prognostic factor in esophageal squamous cell carcinoma patients

Hoshino¹,

Matsubara²,

Akutsu³

et al. 2007

Oncol Rep

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Abstract. Peroxiredoxins (Prdxs) are a family of antioxidant enzymes that are also known as scavengers of peroxide in mammalian cells. Some reports have shown that the overexpression of Prdx1, which is one of the peroxiredoxins that is a ubiquitously expressed protein, was related to a poor prognosis in several types of human cancers. In this study, we investigated the expression levels of Prdx1 in esophageal squamous cell carcinoma by immunohistochemistry, and the correlation between the Prdx1 expression and the clinical status was elucidated. Immunohistochemical staining was performed in 114 samples which were collected from surgical esophageal cancer specimens. Cytoplasmic staining of Prdx1 was evaluated based on the following scoring criteria: Grade I, negative or weak staining; Grade II, moderate staining; and Grade III, strong staining. The percentage of patients with a Grade I expression of Prx1 was 20% (23 of 114), 44% had Grade II (50 of 114), and 36% had Grade III (41 of 114). The Prdx1 immunoreactivity showed an inverse significant correlation with T-category (P<0.0001), lymph node metastasis (P=0.048), and stage (P=0.001). In addition, the patients with tumors exhibiting a reduced Prdx1 expression had shorter overall survival (P=0.022) in comparison to the patients with tumors which had a higher Prdx1 expression. Currently, Prdx1 has been shown to act as a tumor suppressor. Our results provide strong evidence that the reduced Prdx1 expression is an important factor in esophageal squamous cancer progression and could serve as a useful prognostic marker. IntroductionEsophageal cancer is the eighth most frequent cancer and the sixth most frequent cause of death from malignant disease in the world (1). Esophageal squamous cell carcinoma (ESCC) is the most common type in Japan (2). A large number of reports about genetic changes in ESCC have already been published, but little is known about the major tumor suppressor genes or major oncogenes in the process of tumor progression of this malignant disease. ESCC is still a fatal malignancy with a 5-year rate of 5% to 20% for advanced stage patients undergoing a curative resection (3). This miserable prognosis for ESCC involves not only the aggressive character of this tumor but also the limited number of useful markers available for diagnostic purposes.Therefore, better markers which indicate the malignant potential of ESCC should help in the prognosis or optimal treatment of the patients suffering from this disease. In this study, we focus on Prdx1, one of the peroxiredoxins (Prdxs) belonging to a novel antioxidant family, which has been reported to be a tumor suppressor gene. Prdx1 has been thought to have an inhibitory function for both c-Abl and c-Myc, of which active forms cause several neoplasms (4,5). Neumann et al (6) showed, using Prdx1 knockout mice, that Prdx1 expression correlated with the reactive oxygen species and the incidence of malignant disease. Moreover, our previous study using a cDNA microarray showed that one of the novel histone deacet...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Tumor suppressor Prdx1 is a prognostic factor in esophageal squamous cell carcinoma patients

Hoshino¹,

Matsubara²,

Akutsu³

et al. 2007

Oncol Rep

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“…Despite this, p21-deletion studies show that p21 is not strictly necessary for HDAC inhibitor mediated protection against oxidative stress and is only necessary for a portion of HDAC inhibitor mediated protection against DNA damage (Langley et al, 2008). Considering the number of putatively protective genes and pathways induced by HDAC inhibition [for example, p21 (Langley et al, 2008), gelsolin (Meisel et al, 2006), HSP70 (Ren et al, 2004), and peroxiredoxin-1 (Hoshino et al, 2005)], these findings are not surprising. Indeed, it is likely that the ability of HDAC inhibition to induce a number, or "cassette," of protective genes and pathways is in part responsible for the broad neuroprotection observed in vivo.…”

Section: Histone Deacetylase Inhibitors As Broadly Effective Neuropromentioning

confidence: 99%

Epigenetics in the Nervous System: Figure 1.

Jiang¹,

Langley²,

Lubin³

et al. 2008

J. Neurosci.

202

138

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It is becoming increasingly clear that epigenetic modifications are critical factors in the regulation of gene expression. With regard to the nervous system, epigenetic alterations play a role in a diverse set of processes and have been implicated in a variety of disorders. Gaining a more complete understanding of the essential components and underlying mechanisms involved in epigenetic regulation could lead to novel treatments for a number of neurological and psychiatric conditions. Key words: epigenetics; chromatin; DNA methylation; histone; transcription; gene Broadly defined, epigenetics is a type of molecular and cellular "memory" that results in stable changes in gene expression without alterations to the DNA sequence itself. It has long been appreciated that transcription is not occurring on naked DNA, but rather in the context of chromatin which requires the orchestrated effort of not only transcription factors, but also the protein complexes that modify chromatin structure. Currently, commonly studied epigenetic "marks" include DNA methylation and histone modifications, which can include methylation, acetylation, ubiquitination, and phosphorylation, as well as others. Methylation status on any given segment of DNA appears to be controlled in large part by DNA methyltransferases (Ooi and Bestor, 2008). A host of enzymes appear to regulate histone modifications including histone acetyltransferases (HATs) and histone deacetylases (HDACs) as well as methyl-transferases and demethylases (Bhaumik et al., 2007). These epigenetic marks result in alterations to the protein and/or DNA components that make up chromatin structure such that the transcriptional potential of a gene or set of genes near a specific locus is changed. Figure 1 provides an overview of chromatin structure and describes two widely studied epigenetic marks. It is becoming increasingly clear that changes in the chromatin architecture are important factors in gene regulation and understanding these molecular processes and their functional outcomes may give new insight into normal neural function and disease. With regard to brain processes, epigenetic alterations are present and appear to be playing a role in a diverse set of functions including learning and memory processes, drug addiction, neurodegeneration, and circadian rhythms. Epigenetic mechanisms have been implicated in specific human disorders including Fragile X syndrome, Rett syndrome, Huntington's disease, schizophrenia, and bipolar disorder. Understanding the molecular components and environmental conditions that cause or result in epigenetic changes may provide unique opportunities to develop novel interventions and therapies to treat a variety of neurological and psychiatric conditions. The role of chromatin-modifying enzymes in learning and memory processesThe role of transcription in long-lasting forms of synaptic plasticity and memory has been actively investigated since initial experiments showing that transcription is required for long-term memory in goldfish nearly 40 years ...

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“…The histone deacetylase inhibitors (HDACIs) were mainly thought to act by modulating the gene expression patterns, including those of genes associated with cell cycle arrest and apoptosis, by inhibiting the activity of histone deacetylases (HDACs) (5). Previous we reported that depsipeptide (FK228) and cyclic hydroxamic acid-containing peptide 31 (CHAP31) have potent antitumor effects against ESCC in vitro and in vivo (6)(7)(8) Numerous studies have demonstrated that microRNAs (miRNAs), non-coding RNAs 21-25 nucleotides in length, control gene expression by targeting mRNAs for cleavage or translational repression (9). These miRNAs are associated with important biological processes, including development, differentiation, apoptosis, and proliferation (9,10).…”

Section: Introductionmentioning

confidence: 99%

Identification of novel molecular targets regulated by tumor suppressive miR-375 induced by histone acetylation in esophageal squamous cell carcinoma

Isozaki

Hoshino

Nohata

et al. 2012

International Journal of Oncology

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Abstract. The aim of this study was to determine whether histone acetylation regulates tumor suppressive microRNAs (miRNAs) in esophageal squamous cell carcinoma (ESCC) and to identify genes which are regulated by these miRNAs. We identified a miRNA that was highly upregulated in an ESCC cell line by cyclic hydroxamic acid-containing peptide 31 (CHAP31), one of the histone deacetylase inhibi-, one of the histone deacetylase inhibitors (HDACIs), using a miRNA array analysis. miR-375 was strongly upregulated by CHAP31 treatment in an ESCC cell line. The expression levels of the most upregulated miRNA, miR-375 were analyzed by quantitative real-time PCR in human ESCC specimens. The tumor suppressive function of miR-375 was revealed by restoration of miR-375 in ESCC cell lines. We performed a microarray analysis to identify target genes of miR-375. The mRNA and protein expression levels of these genes were verified in ESCC clinical specimens. LDHB and AEG-1/MTDH were detected as miR-375-targeted genes. The restoration of miR-375 suppressed the expression of LDHB and AEG-1/MTDH. The ESCC clinical specimens exhibited a high level of LDHB expression at both the mRNA and protein levels. A loss-of-function assay using a siRNA analysis was performed to examine the oncogenic function of the gene. Knockdown of LDHB by RNAi showed a tumor suppressive function in the ESCC cells. The correlation between gene expression and clinicopathological features was investigated by immunohistochemistry for 94 cases of ESCC. The positive staining of LDHB correlated significantly with lymph node metastasis and tumor stage. It also had a tendency to be associated with a poor prognosis. Our results indicate that HDACIs upregulate miRNAs, at least some of which act as tumor suppressors. LDHB, which is regulated by the tumor suppressive miR-375, may therefore act as an oncogene in ESCC.

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Histone Deacetylase Inhibitor FK228 Activates Tumor Suppressor Prdx1 with Apoptosis Induction in Esophageal Cancer Cells

Cited by 56 publications

References 38 publications

Tumor suppressor Prdx1 is a prognostic factor in esophageal squamous cell carcinoma patients

Tumor suppressor Prdx1 is a prognostic factor in esophageal squamous cell carcinoma patients

Epigenetics in the Nervous System: Figure 1.

Identification of novel molecular targets regulated by tumor suppressive miR-375 induced by histone acetylation in esophageal squamous cell carcinoma

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