Transcriptional induction of DLC-1 gene through Sp1 sites by histone deacetylase inhibitors in gastric cancer cells

Kim, Tai Young; Kim, In Sook; Jong, Hyun Soon; Lee, Sang Eun; Kim, Tae You; Jung, Mira; Bang, Yung Jue

doi:10.3858/emm.2008.40.6.639

Cited by 16 publications

(8 citation statements)

References 29 publications

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“…Several studies have shown interactions of Sp1 with a variety of proteins, including p107, class I HDACs (HDAC1, HDAC2, and HDAC6), p300, and CBP (20,24,25,28,34,53,61). Modulation of the interactions between Sp1 and these partner proteins has been shown to be crucial for the regulation of Sp1-dependent gene expression.…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that corepressors such as HDAC1, HDAC2, and HDAC6 may be recruited by Sp1 to repress gene expression (7,9,25,34). On the other hand, coactivators such as p300 and CBP also could be recruited by Sp1 to the promoters to transactivate gene expression (20,28). We sought to determine which corepressors or coactivators interact with Sp1.…”

Section: Fig 4 Dna Binding Ability Of Sp1 Is Essential For Zp Activmentioning

confidence: 99%

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Interplay between PKCδ and Sp1 on Histone Deacetylase Inhibitor-Mediated Epstein-Barr Virus Reactivation

Tsai

Lin

Weng

et al. 2011

J Virol

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Epstein-Barr virus (EBV) undergoes latent and lytic replication cycles, and its reactivation from latency to lytic replication is initiated by expression of the two viral immediate-early transactivators, Zta and Rta. In vitro, reactivation of EBV can be induced by anti-immunoglobulin, tetradecanoyl phorbol acetate, and histone deacetylase inhibitor (HDACi). We have discovered that protein kinase C delta (PKC␦) is required specifically for EBV reactivation by HDACi. Overexpression of PKC␦ is sufficient to induce the activity of the Zta promoter (Zp) but not of the Rta promoter (Rp). Deletion analysis revealed that the ZID element of Zp is important for PKC␦ activation. Moreover, the Sp1 putative sequence on ZID is essential for PKC␦-induced Zp activity, and the physiological binding of Sp1 on ZID has been confirmed. After HDACi treatment, activated PKC␦ can phosphorylate Sp1 at serine residues and might result in dissociation of the HDAC2 repressor from ZID. HDACi-mediated HDAC2-Sp1 dissociation can be inhibited by the PKC␦ inhibitor, Rotterlin. Furthermore, overexpression of HDAC2 can suppress the HDACi-induced Zp activity. Consequently, we hypothesize that HDACi induces PKC␦ activation, causing phosphorylation of Sp1, and that the interplay between PKC␦ and Sp1 results in the release of HDAC2 repressor from Zp and initiation of Zta expression.Epstein-Barr virus (EBV), a human oncogenic virus, infects two types of human cells predominantly, B lymphocytes and epithelial cells, and EBV infection also is associated with an array of malignancies derived from these two cell types, including Burkitt's lymphoma, Hodgkin's lymphoma, nasopharyngeal carcinoma, and gastric carcinoma (49). Being a human gammaherpesvirus, EBV undergoes two cycles: latency and lytic replication. Although most latent products are important for its ability to immortalize cells, and the virus is present in a latent form in most EBV-associated cancer tissues, serological studies revealed that elevated antibody titers against some lytic antigens, or increased viral DNA load in serum, are risk factors for tumor development (8,33). In addition, experiments using the SCID mouse model suggested that Zta, an EBV lytic transactivator, is crucial for tumor formation (43). In vitro, experimental approaches also revealed that EBV lytic products may contribute to the pathogenesis of EBV-associated diseases, via upregulation of cytokines, cell growth factors or antiapoptotic proteins (5, 48, 50). Thus, the reactivation of EBV not only leads to the production of viral progeny but also facilitates viral pathogenesis.In vitro, EBV persists predominantly in a latent form in host cells. However, lytic replication can be elicited conditionally by many different chemicals and physical stimuli or by ectopic transfection with two transactivators, Zta or Rta (49). These inducing agents provide the best available models for the study of essential factors involved in the switch of EBV from latency to lytic replication. Tetradecanoyl phorbol acetate (TPA) and anti-Ig are...

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Section: Discussionmentioning

confidence: 99%

Section: Fig 4 Dna Binding Ability Of Sp1 Is Essential For Zp Activmentioning

confidence: 99%

Interplay between PKCδ and Sp1 on Histone Deacetylase Inhibitor-Mediated Epstein-Barr Virus Reactivation

Tsai

Lin

Weng

et al. 2011

J Virol

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“…5-Aza-dC has previously been shown to induce overexpression of TSGs by decreasing DNA methylation levels [21,22]. TSA increases the pool of acetylated histones and also induces the overexpression of some TSGs in embryonic stem cells [23,24]. In recent reports, histone H3 lysine 9 (H3K9) methylation and DNA methylation were considered to be the causes of TSG silencing [25].…”

Section: Introductionmentioning

confidence: 99%

Epigenetic inactivation of the tumor suppressor gene RIZ1 in hepatocellular carcinoma involves both DNA methylation and histone modifications

Zhang¹,

Li²,

Wang³

et al. 2010

Journal of Hepatology

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“…Recently, a study providing clues for the mechanism responsible for the induction of DLC1 expression through HDAC-mediated chromatin modifications demonstrated that TSA activates DLC1 promoter in gastric cancer cells and that Sp1 binding sites are required for promoter activation (13).…”

Section: Discussionmentioning

confidence: 99%

Synergistic antineoplastic effect of DLC1 tumor suppressor protein and histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), on prostate and liver cancer cells: Perspectives for therapeutics

Zhou

Yang²,

Popescu³

2010

Int J Oncol

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Abstract. Inactivation of tumor suppressor genes is a major contributing alteration in the initiation or progression of cancer. The human tumor suppressor gene DLC1 (deleted in liver cancer 1) is frequently downregulated or silenced in multiple cancers, predominantly by epigenetic mechanisms. With the current considerable interest and progress in epigenetic therapy, a number of promising antineoplastic agents, particularly histone deacetylase (HDAC) inhibitors, have been developed and used successfully in clinical trials. Both DLC1 and HDAC inhibitors exert antineoplastic functions, and their combined action could be exploited for a more effective cancer therapy. To evaluate the potential benefits of this approach, we examined the antineoplastic effects of adenoviral (Ad)-DLC1-mediated transduction and exposure to suberoylanilide hydroxamic acid (SAHA), a powerful HDAC inhibitor, in two human cancer cell lines that lack intrinsic DLC1 expression, 22Rv1 prostate cancer cells and 7703K human hepatocellular carcinoma cells. Consistent with the oncosuppressive function of DLC1 in several cancers, including prostate and liver cancer, transduction of 22Rv1 and 7703K cells with an Ad-DLC1 expression vector resulted in alterations of cell morphology, induction of apoptosis, and inhibition of cell proliferation, migration, and anchorage-independent growth. A low concentration of SAHA (5 μM) efficiently restored the expression of DLC1 in 22Rv1 cells that lack DLC1 expression due to histone deacetylation but had a minimal effect in 7703K cells in which silencing of the DLC1 gene is due mainly to promoter hypermethylation. Regardless of the epigenetic mechanism of DLC1 inactivation, SAHA treatment of DLC1-transduced cells had a synergistic inhibitory effect on tumor cell proliferation and tumorigenesis in both cell lines. In 22Rv1 cells, this combination regimen nearly abolished the formation of colonies in semisolid media as a measure of tumorigenicity in vitro. Current in vitro results validate this protocol as a potentially new therapeutic option in certain cancers.

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Transcriptional induction of DLC-1 gene through Sp1 sites by histone deacetylase inhibitors in gastric cancer cells

Cited by 16 publications

References 29 publications

Interplay between PKCδ and Sp1 on Histone Deacetylase Inhibitor-Mediated Epstein-Barr Virus Reactivation

Interplay between PKCδ and Sp1 on Histone Deacetylase Inhibitor-Mediated Epstein-Barr Virus Reactivation

Epigenetic inactivation of the tumor suppressor gene RIZ1 in hepatocellular carcinoma involves both DNA methylation and histone modifications

Synergistic antineoplastic effect of DLC1 tumor suppressor protein and histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), on prostate and liver cancer cells: Perspectives for therapeutics

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