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Nuclear heparanase-1 activity suppresses melanoma progression via its DNA-binding affinity

Oncogene volume 34, pages 5832–5842 (2015)Cite this article

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Abstract

Heparanase-1 (HPSE) plays a pivotal role in structural remodeling of the ECM and the glycocalyx, thus conferring protumorigenic, proangiogenic and prometastatic properties to many cancer entities. In addition to its extracellular function, recent studies suggest an intracellular activity of HPSE with a largely unknown significance during tumor progression. Therefore, we investigated the relevance of the dual functions of HPSE to malignant melanoma in vitro, as well as in different mouse melanoma models based on the intradermal or intravenous injection of melanoma cells. Consistent with its extracellular action, an HPSE deficiency led to a reduced shedding of the glycocalyx accompanied by a reduced availability of vascular endothelial growth factor, affecting tumor growth and vascularization. In contrast, we measured an elevated expression of the protumorigenic factors pentraxin-3, tissue factor, TNF-α and most prominently, MMP-9, upon HPSE knockdown. In vivo, an HPSE deficiency was related to increased lymph node metastasis. Since the inhibition of its extracellular function with heparin was unable to block the gene regulatory impact of HPSE, we proposed an intracellular mechanism. Immunostaining revealed a counter-staining of HPSE and NF-κB in the nucleus, suggesting a close relationship between both proteins. This finding was further supported by the discovery of a direct charge-driven molecular interaction between HPSE and DNA by using atomic force microscopy and a co-precipitation approach. Our findings are novel and point towards a dual function for HPSE in malignant melanoma with a protumorigenic extracellular activity and a tumor-suppressive nuclear action. The identification of molecular strategies to shuttle extracellular HPSE into the nuclei of cancer cells could provide new therapeutic options.

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Acknowledgements

We thank Katja Oehme for the excellent technical help and advice in dynamic contrast-enhanced magnetic resonance imaging experiments. We acknowledge Prof. Viktor Umansky (Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany) for providing a melanoma cell line from ret transgenic mice. This work was supported by the Deutsche Forschungsgemeinschaft within the SFB/Transregio 23 (project A9 to SWS, project Z1 to DK).

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  1. Y Yang and C Gorzelanny: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Dermatology, Experimental Dermatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

    Y Yang, C Gorzelanny, A T Bauer, N Halter & S W Schneider

  2. Division of Medical Physics in Radiology, German Cancer Research Center (DKFZ), Heidelberg, Germany

    D Komljenovic

  3. Institute of Radiology, University Hospital Erlangen, Erlangen, Germany

    T Bäuerle

  4. Institute of Physiology, University of Zürich and Zürich Center for Integrative Human Physiology, Zürich, Switzerland

    L Borsig & M Roblek

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Correspondence to S W Schneider.

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Yang, Y., Gorzelanny, C., Bauer, A. et al. Nuclear heparanase-1 activity suppresses melanoma progression via its DNA-binding affinity. Oncogene 34, 5832–5842 (2015). https://doi.org/10.1038/onc.2015.40

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