Inhibition of lymphangiogenic factor VEGF-C expression and production by the histone deacetylase inhibitor suberoylanilide hydroxamic acid in breast cancer cells

Cheng, Hsueh-Tsen; Hung, Wen‐Chun

doi:10.3892/or.2012.2188

Cited by 10 publications

(7 citation statements)

References 33 publications

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“…Evaluation of multiple organ toxicity revealed that prolonged Mith treatment (0.2 mg/kg) was well tolerated with minimal reduction of body weight upon systemic administration to cervical cancer-bearing mice. Along with recent studies on breast37, prostate29, and ovarian cancers38, our results suggest that Mith is be a good therapeutic candidate for treatment of cancers in which Sp1 is important for promoting and developing disease.…”

Section: Discussionsupporting

confidence: 78%

Modulation of specificity protein 1 by mithramycin A as a novel therapeutic strategy for cervical cancer

Choi

Nam

Jung

et al. 2014

Sci Rep

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Cervical cancer is the third most common cancer and the third leading cause of death among women. However, the standard treatment for cervical cancer includes cisplatin, which can cause side effects such as hematological damage or renal toxicity. New innovations in cervical cancer treatment focus on developing more effective and better-tolerated therapies such as Sp1-targeting drugs. Previous studies suggested that mithramycin A (Mith) inhibits the growth of various cancers by decreasing Sp1 protein. However, how Sp1 protein is decreased by Mith is not clear. Few studies have investigated the regulation of Sp1 protein by proteasome-dependent degradation as a possible control mechanism for the regulation of Sp1 in cancer cells. Here, we show that Mith decreased Sp1 protein by inducing proteasome-dependent degradation, thereby suppressing cervical cancer growth through a DR5/caspase-8/Bid signaling pathway. We found that prolonged Mith treatment was well tolerated after systemic administration to mice carrying cervical cancer cells. Reduction of body weight was minimal, indicating that Mith was a good therapeutic candidate for treatment of cancers in which Sp1 is involved in promoting and developing disease.

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Section: Discussionsupporting

confidence: 78%

Modulation of specificity protein 1 by mithramycin A as a novel therapeutic strategy for cervical cancer

Choi

Nam

Jung

et al. 2014

Sci Rep

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“…Thus, both cancer cells and LECs are important for lymphangiogenesis. We recently demonstrated that SAHA attenuated the expression and production of VEGF-C in breast cancer cells (31). We now demonstrate that SAHA also suppresses the proliferation, sprouting and tube formation of LECs.…”

Section: Discussionsupporting

confidence: 52%

Inhibition of proliferation, sprouting, tube formation and Tie2 signaling of lymphatic endothelial cells by the histone deacetylase inhibitor SAHA

Cheng

Hung

2013

Oncology Reports

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Histone deacetylase (HDAC) inhibitors exert potent inhibitory effects on various types of human cancer. The pioneer drug suberoylanilide hydroxamic acid (SAHA) is currently used in the clinic for cancer treatment. However, the effect of SAHA on tumor lymphangiogenesis is unclear. We recently showed that SAHA suppresses the expression and production of pro-lymphagenic factor vascular endothelial growth factor‑C (VEGF-C) in breast cancer cells. In the present study, the effect of SAHA on lymphatic endothelial cells (LECs) was examined. We generated a lymphatic-like endothelial cell line (named FP01) by overexpressing the master LEC transcription factor PROX1 in EA.hy926 endothelial cells. This cell line exhibited a gene expression pattern and phenotype similar to primarily cultured LECs. SAHA inhibited cell cycle progression and proliferation of FP01 cells. In addition, SAHA suppressed sprouting and tube formation in these cells. Moreover, SAHA attenuated the angiopoietin (Ang)/Tie signaling pathway which plays important roles in the regulation of LEC function. FP01 cells expressed Ang1, Ang2, Tie1 and Tie2, and SAHA dose-dependently reduced the expression of Tie2 in these cells. Tie2 promoter activity was attenuated by SAHA indicating a transcriptional repression. Importantly, Tie2 protein was significantly reduced by SAHA at the concentration in which no alteration of Tie2 mRNA was detected. We found that SAHA enhanced Tie2 protein degradation via the ubiquitin-proteasome pathway, and the expression of c-Cbl, the E3 ligase for Tie2 ubiquitination, rapidly increased after SAHA treatment. Knockdown of c-Cbl reversed SAHA‑induced Tie2 protein degradation. Taken together, our results demonstrate that SAHA impairs the proliferation, sprouting and tube formation of LECs and attenuates Ang/Tie signaling in LECs by downregulating Tie-2 via transcriptional and post-transcriptional mechanisms.

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“…VEGF-C and angiopoietin-2) in the oral cancer cell line HSC-3 [ 31 ]. Furthermore, Cheng and Hung found that SAHA, a potent HDACi, inhibits VEGF-C expression in breast cancer cells via Sp1-dependent transcriptional repression [ 32 ]. To date, however, little is known about the effects of HDACi on primary human lymphatic endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

The histone deacetylase inhibitor trichostatin a decreases lymphangiogenesis by inducing apoptosis and cell cycle arrest via p21-dependent pathways

et al. 2016

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BackgroundThe formation of new lymphatic vessels provides an additional route for tumour cells to metastasize. Therefore, inhibiting lymphangiogenesis represents an interesting target in cancer therapy. First evidence suggests that histone deacetylase inhibitors (HDACi) may mediate part of their antitumor effects by interfering with lymphangiogenesis. However, the underlying mechanisms of HDACi induced anti-lymphangiogenic properties are not fully investigated so far and in part remain unknown.MethodsHuman lymphatic endothelial cells (LEC) were cultured in vitro and treated with or without HDACi. Effects of HDACi on proliferation and cell cycle progress were analysed by BrdU assay and flow cytometry. Apoptosis was measured by quantifying mono- and oligonucleosomes in the cytoplasmic fraction of cell lysates. In vitro lymphangiogenesis was investigated using the Matrigel short term lymphangiogenesis assay. The effects of TSA on cell cycle regulatory proteins and apoptosis-related proteins were examined by western blotting, immunofluorescence staining and semi-quantitative RT-PCR. Protein- and mRNA half-life of p21 were analysed by western blotting and quantitative RT-PCR. The activity of the p21 promoter was determined using a dual luciferase assay and DNA-binding activity of Sp1/3 was investigated using EMSA. Furthermore, siRNA assays were performed to analyse the role of p21 and p53 on TSA-mediated anti-lymphangiogenic effects.ResultsWe found that HDACi inhibited cell proliferation and that the pan-HDACi TSA induced G0/G1 arrest in LEC. Cell cycle arrest was accompanied by up-regulation of p21, p27 and p53. Additionally, we observed that p21 protein accumulated in cellular nuclei after treatment with TSA. Moreover, we found that p21 mRNA was significantly up-regulated by TSA, while the protein and mRNA half-life remained largely unaffected. The promoter activity of p21 was enhanced by TSA indicating a transcriptional mechanism. Subsequent EMSA analyses showed increased constitutive Sp1/3-dependent DNA binding in response to HDACi. We demonstrated that p53 was not required for TSA induced p21 expression and growth inhibition of LECs. Interestingly, siRNA-mediated p21 depletion almost completely reversed the anti-proliferative effects of TSA in LEC. In addition, TSA induced apoptosis by cytochrome c release contributed to activating caspases-9, −7 and −3 and downregulating the anti-apoptotic proteins cIAP-1 and −2.ConclusionsIn conclusion, we demonstrate that TSA - a pan-HDACi - has distinct anti-lymphangiogenic effects in primary human lymphatic endothelial cells by activating intrinsic apoptotic pathway and cell cycle arrest via p21-dependent pathways.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2807-y) contains supplementary material, which is available to authorized users.

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Inhibition of lymphangiogenic factor VEGF-C expression and production by the histone deacetylase inhibitor suberoylanilide hydroxamic acid in breast cancer cells

Cited by 10 publications

References 33 publications

Modulation of specificity protein 1 by mithramycin A as a novel therapeutic strategy for cervical cancer

Modulation of specificity protein 1 by mithramycin A as a novel therapeutic strategy for cervical cancer

Inhibition of proliferation, sprouting, tube formation and Tie2 signaling of lymphatic endothelial cells by the histone deacetylase inhibitor SAHA

The histone deacetylase inhibitor trichostatin a decreases lymphangiogenesis by inducing apoptosis and cell cycle arrest via p21-dependent pathways

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