Heparanase Regulates Levels of Syndecan-1 in the Nucleus
Heparanase Regulates Levels of Syndecan-1 in the Nucleus
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DOI：
10.1371/journal.pone.0004947
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发表时间：
2009-03-23
期刊：
影响因子：
3.7
通讯作者：
Sanderson, Ralph D.
中科院分区：
文献类型：
--
作者：
Chen, Ligong;Sanderson, Ralph D.
Syndecan-1是一种跨膜硫酸乙酰肝素蛋白聚糖，已知其调节细胞表面和细胞外基质内的多种生物学功能。它的功能活性可以通过乙酰肝素酶调节，乙酰肝素酶是一种切割硫酸乙酰肝素链的酶，其表达与许多癌症中的侵袭性表型相关。除了通过切割其硫酸乙酰肝素链来重塑多配体蛋白聚糖-1之外，乙酰肝素酶还通过上调加速其从细胞表面脱落的酶的表达来影响多配体蛋白聚糖-1的位置。在目前的研究中，我们发现，乙酰肝素酶也改变核syndecan-1的水平。在上调乙酰肝素酶表达或向骨髓瘤细胞中加入重组乙酰肝素酶后，syndecan-1的核定位显著下降，如通过共聚焦显微镜、蛋白质印迹和ELISA定量所揭示的。这种作用需要酶活性的乙酰肝素酶，因为表达高水平突变的、酶失活的乙酰肝素酶的细胞未能减少细胞核中的多配体蛋白聚糖-1水平。虽然硫酸乙酰肝素在细胞核内的功能还不清楚，但有证据表明它可能抑制转录活性。由核多配体蛋白聚糖-1的丢失促进的基因表达的变化可以解释乙酰肝素酶如何增强MMP-9、VEGF、组织因子和可能调节肿瘤微环境以促进侵袭性癌症表型的其他效应物的表达。
Syndecan-1 is a transmembrane heparan sulfate-bearing proteoglycan known to regulate multiple biological functions at the cell surface and within the extracellular matrix. Its functional activity can be modulated by heparanase, an enzyme that cleaves heparan sulfate chains and whose expression has been associated with an aggressive phenotype in many cancers. In addition to remodeling syndecan-1 by cleaving its heparan sulfate chains, heparanase influences syndecan-1 location by upregulating expression of enzymes that accelerate its shedding from the cell surface. In the present study we discovered that heparanase also alters the level of nuclear syndecan-1. Upon upregulation of heparanase expression or following addition of recombinant heparanase to myeloma cells, the nuclear localization of syndecan-1 drops dramatically as revealed by confocal microscopy, western blotting and quantification by ELISA. This effect requires enzymatically active heparanase because cells expressing high levels of mutated, enzymatically inactive heparanase, failed to diminish syndecan-1 levels in the nucleus. Although heparan sulfate function within the nucleus is not well understood, there is emerging evidence that it may act to repress transcriptional activity. The resulting changes in gene expression facilitated by the loss of nuclear syndecan-1 could explain how heparanase enhances expression of MMP-9, VEGF, tissue factor and perhaps other effectors that condition the tumor microenvironment to promote an aggressive cancer phenotype.