Epigenetic silencing of HSulf-1 in ovarian cancer:implications in chemoresistance

Staub, Julie; Chien, Jeremy; Pan, Yuhang; Qian, Xiang; Narita, Keishi; Aletti, Giovanni; Scheerer, Markus; Roberts, Lewis R.; Molina, Julian R.; Shridhar, Viji

doi:10.1038/sj.onc.1210300

Cited by 95 publications

(88 citation statements)

References 40 publications

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“…Immunoprecipitated DNA was analyzed by q-PCR using promoter-specific primer pairs for two NF-jBbinding sites I and II in miR-146a promoter listed in Table S2 (Supporting information). The negative control primers, flanking a region of genomic DNA between GAPDH gene and the chromosome condensation-related structural maintenance of chromosomes (SMC)-associated protein (CNAP1) gene, were used to represent specificity of ChIP reactions (Staub et al, 2007). The DNA purified from the sonicated nuclear lysate was analyzed by q-PCR using the same primer sets, which was used as an input control.…”

Section: Chip Assay and Q-chip Pcrmentioning

confidence: 99%

Dysregulated expression of miR‐146a contributes to age‐related dysfunction of macrophages

Jiang¹,

Xiang²,

Wang

et al. 2011

Aging Cell

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SummaryAge-associated immune dysfunction, characterized by increased systemic levels of cytokines, manifests as an increased susceptibility to infections. Thus, understanding these negative regulators of the immune response has paved the way to delineating signaling pathways that impact immune senescence. In the present study, we found that miR-146a, which negatively regulated the expression of IL-1b and IL-6, was highly expressed in aged mice. However, there was a lack of response to the stimulation of lipopolysaccharide (LPS) and proinflammatory cytokines in macrophages of aged mice. As a result, the negative feedback regulation loop with miR-146a involving down-regulation of inflammation factors was interrupted in aged mice. Aberrant NF-jB binding to the miR-146a promoter was demonstrated to be associated with the abnormal expression of miR-146a in aged mice. The DNA methyltransferase inhibitor (5-aza-2-deoxycytidine) and the histone deacetylase inhibitor [trichostatin A (TSA)] both significantly up-regulated miR-146a transcriptional activation by altering the DNA-binding activity of NF-jB in macrophages isolated from aged mice, which suggests that DNA methylation and histone acetylation are involved in the suppression of age-dependent miR-146a expression. Additionally, high levels of histone deacetylase (HDACs) expressions contributed to the inhibition of miR-146a expression in LPS-stimulated macrophages from aged mice in vitro. While the suppression of HDACs activities by TSA could improve LPS-induced inflammatory responses owing to up-regulation of miR-146a expression in macrophages from aged mice. These data indicate that the dysregulated expression of miR-146a results in the age-associated dysfunction of macrophages, and miR-146a may be a good target for the treatment of age-related inflammatory diseases.

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Section: Chip Assay and Q-chip Pcrmentioning

confidence: 99%

Dysregulated expression of miR‐146a contributes to age‐related dysfunction of macrophages

Jiang¹,

Xiang²,

Wang

et al. 2011

Aging Cell

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“…Re-expression of HSulf-1 diminishes signaling of various heparin-binding growth factors, decreases cell proliferation, invasion and enhances drug-induced apoptosis in vitro (7)(8)(9)13). Some studies also showed that HSulf-1 could inhibit tumorigenesis and angiogenesis, and promote drug-induced apoptosis in vivo (10)(11)(12).…”

Section: Discussionmentioning

confidence: 99%

“…HSulf-1 could change HSPG-related signaling pathways, such as heparinbinding epidermal growth factor (HB-EGF), fibroblast growth factor-2 (FGF-2), hepatocyte growth factor (HGF), and vascular endothelial growth factor (VEGF). Therefore, dysregulation of HSulf-1 may exert significant effect on cell growth, angiogenesis and tumorigenesis (7)(8)(9)(10)(11)(12)(13)(14). Previous studies have identified HSulf-1 as a downregulated gene in some tumor types including ovarian cancer, hepatocellular cancer, and head and neck squamous cell carcinoma (7,8).…”

Section: Introductionmentioning

confidence: 99%

The enhanced antitumor effects of biodegradable cationic heparin-polyethyleneimine nanogels delivering HSulf-1 gene combined with cisplatin on ovarian cancer

Liu

Gou

et al. 2012

International Journal of Oncology

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Abstract. HSulf-1 (heparan sulfate 6-O-endosulfatase 1), a commonly downregulated gene in the majority of ovarian cancer cell lines, has been identified to play an important role in regulating tumorigenesis. Our previous studies demonstrated that HSulf-1 could inhibit angiogenesis and tumorigenesis in vivo. The employment of polymeric nanoparticles to deliver functional gene holds much promise as an effective therapeutic strategy against ovarian cancer. To develop more effective therapy, in this study, we investigated the antitumor effect of heparin-polyethyleneimine (HPEI) nanogels delivering HSulf-1 combined with cisplatin (DDP) on ovarian cancer. Expression of HSulf-1 in vitro and in vivo was determined by reverse transcription polymerase chain reaction (RT-PCR) and western blot analysis. A SKOV3 intraperitoneal ovarian carcinomatosis model in nude mice was established to assess the antitumor efficacy. Mice were treated with NS, pEP/HPEI complexes, pHSulf-1/HPEI complexes, DDP or pHSulf-1/HPEI plus DDP, respectively. Intraperitoneal tumors were weighed. Antiangiogenic effect in vivo was evaluated by CD31 immunostaining and alginate-encapsulate tumor cell assay. Detection of the proliferative cells and apoptotic cells in tumor tissues were performed by Ki-67 staining and TUNEL assay. Stable expression of HSulf-1 was detected in the pHSulf-1/HPEI and pHSulf-1/HPEI plus DDP groups. The combination of pHSulf-1/HPEI complexes with DDP exhibited enhanced antitumor activity, compared with the monotherapy of HSulf-1 or DDP alone (P<0.01). the combination therapy exerted significant antitumor activity through enhanced antiangiogenesis, induction of apoptosis and suppression of cell proliferation. Collectively, these observations provide evidence that HPEI nanogels delivering HSulf-1 combined with DDP may have a promising application in the therapy of human ovarian cancer.

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“…The upregulation of cellsurface HSPG glypican-1 and syndecan-1 has been described in malignant breast cancer tissue 8 , whilst depletion of the extracellular sulfatase Sulf-1 was reported. 9 Disruption of HS biosynthetic enzymes results in changes in HS fine structure that critically affect cell-matrix interactions, cell signaling and tumor cell behavior, including proliferation, adhesion, migration and apoptosis through interplay of complex mechanisms. 10 Recent studies highlight an aberrant modulation of 3-OST gene expression through epigenetic mechanisms in various tumors including breast, lung, brain, pancreatic, skin and colorectal cancers, suggesting an important role in these pathological conditions.…”

Section: Introductionmentioning

confidence: 99%

The heparan sulfate sulfotransferase 3-OST3A (HS3ST3A) is a novel tumor regulator and a prognostic marker in breast cancer

et al. 2016

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The heparan sulfate sulfotransferase 3-OST3A (HS3ST3A) is a novel tumor regulator and a prognostic marker in breast cancer Mao, X.; Gauche, C.; Coughtrie, M. W. H.; Bui, C.; Gulberti, S.; Merhi-Soussi, F. Citation for published version (APA):Mao, X., Gauche, C., Coughtrie, M. W. H., Bui, C., Gulberti, S., Merhi-Soussi, F., ... Fournel-Gigleux, S. (2016). The heparan sulfate sulfotransferase 3-OST3A (HS3ST3A) is a novel tumor regulator and a prognostic marker in breast cancer. Oncogene, 35, 5043-5055. DOI: 10.1038/onc.2016 General rights Copyright and moral rights for the publications made accessible in Discovery Research Portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from Discovery Research Portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain.• You may freely distribute the URL identifying the publication in the public portal. Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Heparan sulfate (HS) proteoglycan chains are key components of the breast tumor microenvironment that critically influence the behavior of cancer cells. It is established that abnormal synthesis and processing of HS play a prominent role in tumorigenesis albeit mechanisms remain mostly obscure. HS function is mainly controlled by sulfotransferases, and here we report a novel cellular and pathophysiological significance for the 3--O--sulfotransferase 3--OST3A (HS3ST3A), catalyzing the final maturation step of HS, in breast cancer. We show that 3--OST3A is epigenetically repressed in all breast cancer cell lines of a panel representative of distinct molecular subgroups, except in HER2--positive (HER2+) SKBR3 cells. Epigenetic mechanisms involved both DNA methylation and histone modifications, producing different repressive chromatin environments depending on the cell molecular signature. Gain and loss of function experiments by cDNA and siRNA transfection revealed profound effects of 3--OST3A expression on cell behavior including apoptosis, proliferation, response to trastuzumab in vitro and tumor growth in xenografted mice. 3--OST3A exerted dual activities acting as tumor--suppressor in lumA--MCF--7 and triple negative--MDA--MB--231 cells, or as an oncogenic factor in HER2+--SKBR3 cells. Mechanistically, fluorescence--resonance energy transfer (FRET)--fluorescence--lifetime imaging microscopy (FLIM) experiments indicated that the effects of 3--OST3A in MCF--7 cells were mediated by altered interactions between HS and fibroblast growth factor--7 (FGF--7). Further, this interplay between HS and FGF--7 modulated downstream ERK, AKT and p38 cascades, suggesting that altering 3--O--sulfation affects FGFR...

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Epigenetic silencing of HSulf-1 in ovarian cancer:implications in chemoresistance

Cited by 95 publications

References 40 publications

Dysregulated expression of miR‐146a contributes to age‐related dysfunction of macrophages

Dysregulated expression of miR‐146a contributes to age‐related dysfunction of macrophages

The enhanced antitumor effects of biodegradable cationic heparin-polyethyleneimine nanogels delivering HSulf-1 gene combined with cisplatin on ovarian cancer

The heparan sulfate sulfotransferase 3-OST3A (HS3ST3A) is a novel tumor regulator and a prognostic marker in breast cancer

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