Epidermal Growth Factor–Induced Heparanase Nucleolar Localization Augments DNA Topoisomerase I Activity in Brain Metastatic Breast Cancer

Zhang, Lixin; Sullivan, Peggy; Suyama, Julie A.; Marchetti, Dario

doi:10.1158/1541-7786.mcr-09-0375

Cited by 50 publications

(64 citation statements)

References 28 publications

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“…S1D). Interestingly, a recent study showed that topoisomerase I activity was augmented in a breast cancer cell line following epidermal growth factor induced elevation of heparanase in the nucleolus (31). Although the mechanism of heparanase-induced augmentation of topoisomerase I was not examined in this study, it will be interesting to determine if it is related to reduced levels of heparan sulfate present within the nucleolus of these cells.…”

Section: Restoration Of High Syndecan-1 Level In Nucleus Decreasesmentioning

confidence: 86%

Heparanase-mediated Loss of Nuclear Syndecan-1 Enhances Histone Acetyltransferase (HAT) Activity to Promote Expression of Genes That Drive an Aggressive Tumor Phenotype

Purushothaman

Hurst

Pisano

et al. 2011

Journal of Biological Chemistry

103

116

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Heparanase acts as a master regulator of the aggressive tumor phenotype in part by enhancing expression of proteins known to drive tumor progression (e.g. VEGF, MMP-9, hepatocyte growth factor (HGF), and RANKL). However, the mechanism whereby this enzyme regulates gene expression remains unknown. We previously reported that elevation of heparanase levels in myeloma cells causes a dramatic reduction in the amount of syndecan-1 in the nucleus. Because syndecan-1 has heparan sulfate chains and because exogenous heparan sulfate has been shown to inhibit the activity of histone acetyltransferase (HAT) enzymes in vitro, we hypothesized that the reduction in nuclear syndecan-1 in cells expressing high levels of heparanase would result in increased HAT activity leading to stimulation of protein transcription. We found that myeloma cells or tumors expressing high levels of heparanase and low levels of nuclear syndecan-1 had significantly higher levels of HAT activity when compared with cells or tumors expressing low levels of heparanase. High levels of HAT activity in heparanase-high cells were blocked by SST0001, an inhibitor of heparanase. Restoration of high syndecan-1 levels in heparanase-high cells diminished nuclear HAT activity, establishing syndecan-1 as a potent inhibitor of HAT. Exposure of heparanase-high cells to anacardic acid, an inhibitor of HAT activity, significantly suppressed their expression of VEGF and MMP-9, two genes known to be up-regulated following elevation of heparanase. These results reveal a novel mechanistic pathway driven by heparanase expression, which leads to decreased nuclear syndecan-1, increased HAT activity, and up-regulation of transcription of multiple genes that drive an aggressive tumor phenotype.Heparanase, an endoglycosidase that cleaves heparan sulfate, is up-regulated in many cancers where it promotes tumor growth, angiogenesis, and metastasis (1, 2). High levels of heparanase in cancer patients are associated with shorter postoperative survival time compared with patients with low levels of heparanase (1). Although some of the tumor promoting effects of heparanase can be attributed to its ability to remodel the extracellular matrix barrier by cleaving heparan sulfate, heparanase is also known to regulate cell signaling and gene transcription (1, 3-5). Elevation of heparanase levels in myeloma cells, either by transfection of cells or by addition of recombinant active heparanase enzyme to cells, up-regulates expression of MMP-9, VEGF, HGF, 2 and RANKL, which together drive an aggressive tumor phenotype (6 -9). Although the mechanism whereby heparanase drives gene expression remains unknown, the enzyme is present and active in the nucleus where it could act locally to regulate gene expression (10).Acetylation of the N-terminal tails of histones by histone acetyltransferase enzymes has been known for many years to be a process correlating with transcriptional activation (11)(12)(13)(14). This process is balanced by the activity of histone deacetylases (HDACs), which selectivel...

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Section: Restoration Of High Syndecan-1 Level In Nucleus Decreasesmentioning

confidence: 86%

Heparanase-mediated Loss of Nuclear Syndecan-1 Enhances Histone Acetyltransferase (HAT) Activity to Promote Expression of Genes That Drive an Aggressive Tumor Phenotype

Purushothaman

Hurst

Pisano

et al. 2011

Journal of Biological Chemistry

103

116

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“…Because heparanase plays a role in cell invasion through the degradation of HSPG in the ECM and BM (18,19), we tested the effect of heparanase RNAi on the invasive ability of HepG2 cells using the Matrigel invasion assay. As shown in Fig.…”

Section: Heparanase Sirna Significantly Inhibits the Invasive Abilitymentioning

confidence: 99%

Downregulation of heparanase by RNA interference inhibits invasion and tumorigenesis of hepatocellular cancer cells in vitro and in vivo

et al. 2012

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Abstract.Heparanase is an endoglycosidase that degrades heparan sulfate, the main polysaccharide constituent of the extracellular matrix and basement membrane. The expression of heparanase is associated with invasion, as well as the angiogenic and metastatic potential of diverse malignant tumors. We used RNA interference strategies to evaluate the role of human heparanase in a liver cancer cell line and to explore the therapeutic potential of its specific targeting. Using an online siRNA tool, we designed three small interfering RNA sequences to target the heparanase coding region and cloned them into the pGenesil-1 vector. The siRNA vectors were transfected into HepG2 liver cancer cells. Heparanase expression was measured by real-time RT-PCR and Western blotting. Cell proliferation was detected by MTT staining and plate colony formation. Cell cycle analysis was performed by flow cytometry. In vitro invasion was measured by Matrigel invasion assay. We also analyzed tumorigenicity in heparanase-suppressed HepG2 cells in nude mice. We found that siRNA-1 (1214-1232) and siRNA-3 (611-629) targeting heparanase significantly downregulated the expression of heparanase in HepG2 liver cancer cells. Compared with its controls, siRNA-1 or siRNA-3 vectors efficiently inhibited the proliferation and invasion of HepG2 liver cancer cells in vitro and tumorigenesis in vivo. These results suggest that heparanase-specific RNA interference has potential value as a novel therapeutic agent for human liver cancer.

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“…Some MMPs have been more thoroughly investigated than others, for example MMP1 has been observed to regulate the levels of transforming growth factor α which in turn affects the activation of EGFR in breast cancer cells [140]. EGFR is relevant to breast cancer as its ligand has been linked to promoting heparanase function and topoisomerase I localization in brain metastasizing breast cancer cells [141]. This information can then facilitate our medical community in development of drugs and treatment, however, to improve it is vital that we pinpoint which MMPs the most critical in breast cancer and how they function during tumor development.…”

Section: Each Variation Of Mmp Has Unique Functionmentioning

confidence: 99%

Role of ESR Pathway Genes in Breast Cancer: A Review

Kumar¹,

Myers²,

Homsi³

et al. 2018

ABCR

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Breast cancer is the leading cause of death in women. Prognosis of breast cancer is often pessimistic because the tumors are prone to metastasizing to the bone, brain, and lung. The estrogen signaling receptor (ESR) pathway contains 39 main genes and proteins which makes it one of the larger signaling pathways. Predominately this pathway and the proteins within are involved in breast growth and development, making it a prospective area of study for breast cancer. While the healthy ESR pathway has been constructed and is well established, a mechanistic model of mutated genes of ESR pathway has not been delved upon. Such mutated models could be utilized for selecting combinational targets for drug therapies, as well as elucidating crosstalk between other pathways and feedback mechanisms. To construct the mutated models of the ESR pathway it is imperative to assess what is currently understood in the literature and what inconsistencies exist in order to resolve them. Without this information, a model of the ESR pathway will be unreliable and likely unproductive. This review is the detailed literature survey of the biological studies performed on ESR pathways genes, and their respective roles in breast cancer. Furthermore, the details mentioned in the review can be beneficial for the integrated study of the ESR pathway genes, which includes, structural and dynamics study of the genes products, to have a holistic understanding of the cancer mechanism.

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Epidermal Growth Factor–Induced Heparanase Nucleolar Localization Augments DNA Topoisomerase I Activity in Brain Metastatic Breast Cancer

Cited by 50 publications

References 28 publications

Heparanase-mediated Loss of Nuclear Syndecan-1 Enhances Histone Acetyltransferase (HAT) Activity to Promote Expression of Genes That Drive an Aggressive Tumor Phenotype

Heparanase-mediated Loss of Nuclear Syndecan-1 Enhances Histone Acetyltransferase (HAT) Activity to Promote Expression of Genes That Drive an Aggressive Tumor Phenotype

Downregulation of heparanase by RNA interference inhibits invasion and tumorigenesis of hepatocellular cancer cells in vitro and in vivo

Role of ESR Pathway Genes in Breast Cancer: A Review

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