Nuclear Heparanase Regulates Chromatin Remodeling, Gene Expression and PTEN Tumor Suppressor Function.
Nuclear Heparanase Regulates Chromatin Remodeling, Gene Expression and PTEN Tumor Suppressor Function.
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DOI：
10.3390/cells9092038
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发表时间：
2020-09-06
期刊：
影响因子：
6
通讯作者：
Sanderson RD
中科院分区：
文献类型：
--
作者：
Amin R;Tripathi K;Sanderson RD
肝素酶(heparanase，HPSE)是一种内切糖苷酶，可分解硫酸肝素，在多种癌症中被发现可促进转移、血管生成、骨溶解和化疗耐药。尽管乙酰肝素酶被认为主要在细胞外或细胞质内发挥作用，但它也存在于细胞核中，在那里它可能起到调节基因转录的作用。在骨髓瘤细胞系中，我们报告了肝素酶增强染色质的可及性，并证实了先前的报告，即它也上调了组蛋白的乙酰化。利用多发性骨髓瘤研究基金会Commpass数据库，我们证明，与低水平肝素酶表达的患者相比，高水平肝素酶表达的患者与染色质重塑相关的蛋白质和几种致癌因子的表达增加。这些特征与乙酰肝素酶在推动肿瘤进展中的已知功能是一致的。乙酰肝素酶抑制后，染色质开放基因和下游靶基因被取消。骨髓瘤细胞中乙酰肝素酶水平的升高导致PTEN的磷酸化显著增加，这一事件可以稳定PTEN，导致其失活和肿瘤抑制功能的丧失。总而言之，这项研究表明，肝素酶促进染色质开放和转录活性，其中一些可能是通过它对PTEN肿瘤抑制活性的影响而实现的。
Heparanase (HPSE) is an endoglycosidase that cleaves heparan sulfate and has been shown in various cancers to promote metastasis, angiogenesis, osteolysis, and chemoresistance. Although heparanase is thought to act predominantly extracellularly or within the cytoplasm, it is also present in the nucleus, where it may function in regulating gene transcription. Using myeloma cell lines, we report here that heparanase enhances chromatin accessibility and confirm a previous report that it also upregulates the acetylation of histones. Employing the Multiple Myeloma Research Foundation CoMMpass database, we demonstrate that patients expressing high levels of heparanase display elevated expression of proteins involved in chromatin remodeling and several oncogenic factors compared to patients expressing low levels of heparanase. These signatures were consistent with the known function of heparanase in driving tumor progression. Chromatin opening and downstream target genes were abrogated by inhibition of heparanase. Enhanced levels of heparanase in myeloma cells led to a dramatic increase in phosphorylation of PTEN, an event known to stabilize PTEN, leading to its inactivity and loss of tumor suppressor function. Collectively, this study demonstrates that heparanase promotes chromatin opening and transcriptional activity, some of which likely is through its impact on diminishing PTEN tumor suppressor activity.
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影响因子：
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作者：
Matsumoto CS;Almeida LO;Guimarães DM;Martins MD;Papagerakis P;Papagerakis S;Leopoldino AM;Castilho RM;Squarize CH
通讯作者：
Squarize CH
影响因子：
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影响因子：
16.6
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影响因子：
11
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