Apoptotic Speck Protein-Like, a Highly Homologous Protein to Apoptotic Speck Protein in the Pyrin Domain, Is Silenced by DNA Methylation and Induces Apoptosis in Human Hepatocellular Carcinoma

Kubo, Takahiko; Yamamoto, Junji; Shikauchi, Yuko; Niwa, Yasuharu; Matsubara, Kazuo; Yoshikawa, H

doi:10.1158/0008-5472.can-03-3314

Cited by 27 publications

(25 citation statements)

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“…Methylation analysis of SOCS-3 and SOCS-1 revealed that SOCS-3 methylation was frequently observed in SOCS-1 methylated samples, suggesting that the critical involvement of SOCS family proteins in the development of cancer. Concomitant methylation was also observed in family genes such that p15 and p16 were methylated in leukemia (Herman et al, 1997), and ASCL and ASC were methylated in HCC (Kubo et al, 2004). SOCS-1 methylation was reported to correlate with severity of liver fibrosis (Yoshida et al, 2004 (Table 1a).…”

Section: Discussionmentioning

confidence: 97%

Methylation silencing of SOCS-3 promotes cell growth and migration by enhancing JAK/STAT and FAK signalings in human hepatocellular carcinoma

et al. 2005

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We identified that suppressor of cytokine signaling-3 (SOCS-3) gene was aberrantly methylated in its CpG island in three of 10 human hepatocellular carcinoma (HCC) cell lines. SOCS-3 RNA was undetectable in five of the 10 HCC cell lines including the three methylated cell lines, and a demethylating agent, 5-aza-2 0 -deoxycytidine, reactivated SOCS-3 expression in three cell lines tested. The DNA region where we found aberrant DNA methylation includes a signal transducers and activators of transcription (STAT) binding consensus sequence. When the DNA region was used as a promoter, DNA methylation markedly reduced promoter activity. SOCS-3 was also aberrantly methylated in six of 18 primary HCC samples. SOCS-3 expression was reduced in three of the three methylated and one of the three unmethylated primary samples examined. Restoration of SOCS-3 in cells lacking SOCS-3 expression suppressed STAT3 phosphorylation and cell growth. We found that IL-6 acted as a growth factor in HCC cells. Inhibition of SOCS-3 expression in cells whose growth was induced by IL-6 enhanced STAT3 phosphorylation and cell growth. In addition, AG490, a chemical JAK2 inhibitor, suppressed cell growth and downregulated STAT3 phosphorylation, but not FAK phosphorylation. We also found that SOCS-3 physically interacted with phosphorylated FAK and Elongin B in HCC cells. Restoration of SOCS-3 decreased FAK phosphorylation as well as FAK protein level. Inhibition of SOCS-3 expression increased FAK phosphorylation, resulting in enhancement of cell migration. These data indicate that SOCS-3 negatively regulates cell growth and cell motility by inhibiting Janus kinase (JAK)/STAT and FAK signalings in HCC cells. Thus, loss of SOCS-3 by the associated DNA methylation confers cells advantage in growth and migration.

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Section: Discussionmentioning

confidence: 97%

Methylation silencing of SOCS-3 promotes cell growth and migration by enhancing JAK/STAT and FAK signalings in human hepatocellular carcinoma

et al. 2005

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“…17,18 In human HCC, a number of methylation-induced inactivation of genes, such as E-cadherin, p16INK4a, 14-3-3 sigma, SOCS-1 and DLC-1, have already been documented. [19][20][21][22][23][24][25][26][27] However, there is no information on the methylation-mediated silencing of Apo D in HCC. Therefore, we first analyzed the pharmacological induction of Apo D by 5-Azacitidine in human liver cancer cell lines.…”

Section: Discussionmentioning

confidence: 99%

Clinicopathologic and prognostic values of apolipoprotein D alterations in hepatocellular carcinoma

Utsunomiya

Ogawa

Yoshinaga

et al. 2005

Intl Journal of Cancer

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We previously identified apolipoprotein D (Apo D) as a novel tumor suppressor gene based on the pharmacological unmasking of epigenetic silencing. We analyzed Apo D expression using realtime reverse transcription-PCR and evaluated its expression status based on the clinicopathological parameters of 70 patients with hepatocellular carcinoma (HCC). Immunohistochemical staining was also performed. We determined the methylation status of Apo D gene promoter by methylation-specific PCR (MSP). The Apo D gene-expression in tumor tissue was significantly lower than that in nontumor tissue (p = 0.011). A low Apo D expression significantly correlated with less-differentiated HCC ( p = 0.019). Immunohistochemical studies confirmed a decreased Apo D expression in poorly differentiated tumors. The prognosis of patients with a lower Apo D gene-expression was significantly worse than that in those with a higher expression (p = 0.028). The Apo D gene-expression was an independent prognostic factor (relative risk: 2.36, p = 0.018). An MSP assay showed a low-level of methylation in well differentiated HCC and a high-level of methylation in less differentiated tumors. Apo D may be a novel tumor suppressor gene of HCC, and its expression status may be a useful biomarker for predicting the patient outcome. ' 2005 Wiley-Liss, Inc.Key words: apolipoprotein D; hepatocellular carcinoma; histological grade; prognostic factor; methylationWe recently performed a comprehensive survey of commonly inactivated tumor suppressor genes in esophageal cancer cell lines based on functional reactivation by a demethylating agent. 1 A total of 58 silenced genes were thus identified using this approach, and one of those genes was Apolipoprotein D (Apo D). In our report, we detected the promoter hypermethylation of Apo D gene using bisulfite DNA sequencing. The methylation status of Apo D correlated closely with the Apo D expression status. Moreover, the growth suppressive activity of Apo D was also demonstrated by a colony focus assay. 1 These findings thus prompted us to analyze the clinical significance of the Apo D expression status in human cancers.Apo D, belonging to the lipocalin superfamily, is a glycoprotein of about 30 kDa found in the high-density lipoprotein fraction of human plasma. 2 The functional role of Apo D remains unclear, but the observation that this protein forms complexes with lecithin-cholesterol acyltransferase suggests that Apo D may be involved in cholesterol esterification. 3 More recently, the Apo D gene-expression was reported to be induced by retinoic acid in breast cancer cell lines. The induction of the Apo D expression was accompanied by an inhibition of cell proliferation and a progression through a more differentiated phenotype. These finding suggest that the mechanisms controlling retinoic acid-induced growth arrest, cell differentiation and Apo D synthesis may be directly coordinated in human breast cancer cells. 4 Furthermore, a low expression of Apo D determined by an immunohistochemical study was significantly as...

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“…Silencing of tumor suppressor genes by methylation is a frequent mechanism of cancer cells to escape growth control and apoptosis. Also the promoter of cPOP1 was found to be methylated in hepatocellular carcinomas, and cPOP1 expression was demonstrated to have growth suppressive and proapoptotic effects [129]. This observation strongly suggests that the PYD of ASC might be the domain responsible for ASC silencing in carcinomas.…”

Section: Silencing Of Pyrin Domain-containing Proteins In Cancermentioning

confidence: 96%

“…Also the promoter of cPOP1 was found to be methylated in hepatocellular carcinomas, and cPOP1 expression was demonstrated to have growth suppressive and proapoptotic effects [129]. This observation strongly suggests that the PYD of ASC might be the domain responsible for ASC silencing in carcinomas.ASC and cPOP1 might be silenced to prevent their effects on signal transduction pathways, and both have been implicated to promote apoptosis [26,27,129]. Because ASC is important for DNA damage-induced apoptosis, loss of its expression might also affect efficiency of anti-tumor therapy.…”

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The PYRIN Domain in Signal Transduction

Stehlik¹

2007

CPPS

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The Death Domain Fold superfamily of evolutionarily conserved protein-protein interaction domains consists of 4 subfamilies: the death domain, the death effector domain, the caspase recruitment domain, and the PYRIN domain. Interaction of Death Domain Fold containing proteins modulates the activity of several downstream effectors, such as caspases and transcription factors. Recent studies provide evidence for not only homotypic-, but also heterotypic interactions among different sub-families, and even unconventional non-death domain fold interactions. As the number of potential protein associations among Death Domain Fold containing proteins expands and their influence on cellular responses increases, a challenging field for new investigations opens up. This review will focus on PYRIN domain-containing proteins and discuss the recent advances that provide strong evidence that PYRIN domain-mediated signal transduction has broad implications on cellular functions, including innate immunity, inflammation, differentiation, apoptosis, and cancer. Keywords apoptosis; cancer; CARD domain; caspase activation; death domain fold; inflammation; interleukin-1; leucine rich region; NACHT domain; NF-κB; pathogen associated molecular pattern; pathogen recognition receptor; PYRIN domain; signal transduction THE DEATH DOMAIN FOLD SUPERFAMILY OF PROTEIN INTERACTION DOMAINSThe death domain fold (DDF) is a highly conserved protein interaction domain spanning approximately 90 amino acid residues. This superfamily consists of four subfamilies: The death domain (DD), the death effector domain (DED), the caspase recruitment domain (CARD), and the pyrin N-terminal homology domain (PYRIN domain, PYD). Subfamilies are mainly defined by sequence homology, and display a common three-dimensional structure. However, the sequence identity between the subfamilies is usually lower than 25%, and even within one family mainly restricted to conserved residues of the hydrophobic core.DDF containing proteins have been linked to the activation of caspases and subsequent initiation of apoptosis by the induced proximity mechanism. However, several additional downstream effectors link these domains not only to apoptosis, but also immunity, NIH Public Access DD-DD, DED-DED, CARD-CARD, PYD-PYD).Yet, recent evidence demonstrated their capability to also form heterotypic interactions among family members, and even unconventional, non-DDF interactions, thereby increasing the number of potential protein associations and cellular responses. The first evidence for unconventional, non-DDF interactions came from the observation that the DED of PEA-15 (PED) interacts with the C-terminal domain of ERK [1]. Also, the DD of Fas (Apo-1, CD95, TNFRSF6) was suggested to associate with calmodulin in a Fas ligand and Ca 2+ -dependent manner [2]. The apoptosis repressor with a CARD (ARC CARD2, Myp) can disrupt the intrinsic, mitochondrial apoptosis pathway by association of its CARD with the C-terminal domain of Bax. By heterotypic interaction, ARC disrupts the ext...

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Apoptotic Speck Protein-Like, a Highly Homologous Protein to Apoptotic Speck Protein in the Pyrin Domain, Is Silenced by DNA Methylation and Induces Apoptosis in Human Hepatocellular Carcinoma

Cited by 27 publications

References 15 publications

Methylation silencing of SOCS-3 promotes cell growth and migration by enhancing JAK/STAT and FAK signalings in human hepatocellular carcinoma

Methylation silencing of SOCS-3 promotes cell growth and migration by enhancing JAK/STAT and FAK signalings in human hepatocellular carcinoma

Clinicopathologic and prognostic values of apolipoprotein D alterations in hepatocellular carcinoma

The PYRIN Domain in Signal Transduction

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