SULF1/SULF2 reactivation during liver damage and tumour growth

Graham, Kurtis; Murphy, Joshua I.; Dhoot, Gurtej K.

doi:10.1007/s00418-016-1425-8

Cited by 14 publications

(13 citation statements)

References 41 publications

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“…Therefore, a contribution to EndMT in this context might be possible. The third gene of interest, SULF1, is a heparan sulfate 6-Oendosulfatase (53), which is important for migration of epithelial cells during wound repair and is activated by liver damage (42,(54)(55)(56). Heparan sulfate proteoglycans localize to the cell surface and the basement membrane and are a component of the extracellular matrix.…”

Section: Discussionmentioning

confidence: 99%

The histone demethylase JMJD2B regulates endothelial-to-mesenchymal transition

Glaser

Heumüller

Tombor

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Endothelial cells play an important role in maintenance of the vascular system and the repair after injury. Under proinflammatory conditions, endothelial cells can acquire a mesenchymal phenotype by a process named endothelial-to-mesenchymal transition (EndMT), which affects the functional properties of endothelial cells. Here, we investigated the epigenetic control of EndMT. We show that the histone demethylase JMJD2B is induced by EndMT-promoting, proinflammatory, and hypoxic conditions. Silencing of JMJD2B reduced TGF-β2-induced expression of mesenchymal genes, prevented the alterations in endothelial morphology and impaired endothelial barrier function. Endothelial-specific deletion of JMJD2B in vivo confirmed a reduction of EndMT after myocardial infarction. EndMT did not affect global H3K9me3 levels but induced a site-specific reduction of repressive H3K9me3 marks at promoters of mesenchymal genes, such as Calponin (CNN1), and genes involved in TGF-β signaling, such as AKT Serine/Threonine Kinase 3 (AKT3) and Sulfatase 1 (SULF1). Silencing of JMJD2B prevented the EndMT-induced reduction of H3K9me3 marks at these promotors and further repressed these EndMT-related genes. Our study reveals that endothelial identity and function is critically controlled by the histone demethylase JMJD2B, which is induced by EndMT-promoting, proinflammatory, and hypoxic conditions, and supports the acquirement of a mesenchymal phenotype.

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Section: Discussionmentioning

confidence: 99%

The histone demethylase JMJD2B regulates endothelial-to-mesenchymal transition

Glaser

Heumüller

Tombor

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…In addition, HS mimetics as well as antibodies, and other modulators have been developed to target heparanase and sulfatases involved in the regulation of HSPGs in tumor microenvironment [92,101,165,251,[260][261][262][263][264][265][266][267][268][269][270]. Indeed, the HS mimetics PI-88, PG545, and M402 have been shown to exert anti-angiogenic and antimetastatic effects by inhibiting heparanase in several types of cancers [89,[224][225][226][227][228][229][230]. Furthermore, heparanase neutralizing monoclonal antibodies attenuate myeloma and lymphoma tumor growth and dissemination [155,251,261,262,265,266].…”

Section: Heparan Sulfate Proteoglycans As Therapeutic Targets For Cancermentioning

confidence: 99%

Heparan Sulfate Proteoglycan Signaling in Tumor Microenvironment

Pasquale

Pavone

2020

IJMS

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In the last few decades, heparan sulfate (HS) proteoglycans (HSPGs) have been an intriguing subject of study for their complex structural characteristics, their finely regulated biosynthetic machinery, and the wide range of functions they perform in living organisms from development to adulthood. From these studies, key roles of HSPGs in tumor initiation and progression have emerged, so that they are currently being explored as potential biomarkers and therapeutic targets for cancers. The multifaceted nature of HSPG structure/activity translates in their capacity to act either as inhibitors or promoters of tumor growth and invasion depending on the tumor type. Deregulation of HSPGs resulting in malignancy may be due to either their abnormal expression levels or changes in their structure and functions as a result of the altered activity of their biosynthetic or remodeling enzymes. Indeed, in the tumor microenvironment, HSPGs undergo structural alterations, through the shedding of proteoglycan ectodomain from the cell surface or the fragmentation and/or desulfation of HS chains, affecting HSPG function with significant impact on the molecular interactions between cancer cells and their microenvironment, and tumor cell behavior. Here, we overview the structural and functional features of HSPGs and their signaling in the tumor environment which contributes to tumorigenesis and cancer progression.

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“…For the first time, we identified the main cellular sources and levels of HSPG2 and SULF1 transcripts in the PCa bone metastatic microenvironment and examined the ability of the proteins they encode to regulate Wnt3A-mediated PCa growth in perlecan-modified hydrogels. Previous reports explored SULF1 expression mostly in cancer cells [56], with the majority showing reduced levels of SULF1 in progressive ovarian, hepatocellular, breast, and head and neck carcinomas [52,[57][58][59][60]. Given that SULFs can act directly to remove 6-O-sulfate from HSPG co-receptors at the cell surface [18,61], it is reasonable to expect that cancer cells would down-regulate their SULF1 expression to escape signaling suppression.…”

Section: Discussionmentioning

confidence: 99%

SULF1 suppresses Wnt3A-driven growth of bone metastatic prostate cancer in perlecan-modified 3D cancer-stroma-macrophage triculture models

et al. 2020

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Bone marrow stroma influences metastatic prostate cancer (PCa) progression, latency, and recurrence. At sites of PCa bone metastasis, cancer-associated fibroblasts and tumor-associated macrophages interact to establish a perlecan-rich desmoplastic stroma. As a heparan sulfate proteoglycan, perlecan (HSPG2) stores and stabilizes growth factors, including heparin-binding Wnt3A, a positive regulator of PCa cell growth. Because PCa cells alone do not induce CAF production of perlecan in the desmoplastic stroma, we sought to discover the sources of perlecan and its growth factor-releasing modifiers SULF1, SULF2, and heparanase in PCa cells and xenografts, bone marrow fibroblasts, and macrophages. SULF1, produced primarily by bone marrow fibroblasts, was the main glycosaminoglycanase present, a finding validated with primary tissue specimens of PCa metastases with desmoplastic bone stroma. Expression of both HSPG2 and SULF1 was concentrated in αSMA-rich stroma near PCa tumor nests, where infiltrating pro-tumor TAMs also were present. To decipher SULF1's role in the reactive bone stroma, we created a bone marrow biomimetic hydrogel incorporating perlecan, PCa cells, macrophages, and fibroblastic bone marrow stromal cells. Finding that M2-like macrophages increased levels of SULF1 and HSPG2 produced by fibroblasts, we examined SULF1 function in Wnt3A-mediated PCa tumoroid growth in tricultures. Comparing control or SULF1 knockout fibroblastic cells, we showed that SULF1 reduces Wnt3A-driven growth, cellularity, and cluster number of PCa cells in our 3D model. We conclude that SULF1 can suppress Wnt3A-driven growth signals in the desmoplastic stroma of PCa bone metastases, and SULF1 loss favors PCa progression, even in the presence of pro-tumorigenic TAMs.

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SULF1/SULF2 reactivation during liver damage and tumour growth

Cited by 14 publications

References 41 publications

The histone demethylase JMJD2B regulates endothelial-to-mesenchymal transition

The histone demethylase JMJD2B regulates endothelial-to-mesenchymal transition

Heparan Sulfate Proteoglycan Signaling in Tumor Microenvironment

SULF1 suppresses Wnt3A-driven growth of bone metastatic prostate cancer in perlecan-modified 3D cancer-stroma-macrophage triculture models

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