Transcriptional regulation of hypoxia-inducible factor 1α by HIPK2 suggests a novel mechanism to restrain tumor growth
Transcriptional regulation of hypoxia-inducible factor 1α by HIPK2 suggests a novel mechanism to restrain tumor growth
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DOI：
10.1016/j.bbamcr.2008.10.013
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发表时间：
2009-02-01
影响因子：
5.1
通讯作者：
D'Orazi, Gabriella
中科院分区：
文献类型：
--
作者：
Nardinocchi, Lavinia;Puca, Rosa;D'Orazi, Gabriella
HIPK 2通过不止一种机制参与抑制肿瘤进展，涉及其催化和转录共阻遏物功能。从发现通过RNA干扰（HIPK 2 i）敲低HIPK 2诱导肿瘤细胞中HIF-1 α mRNA及其靶VEGF的显著上调开始，我们评估了HIPK 2在HIF-1 α转录调节中的作用。我们发现，HIPK 2过表达下调HIF-1 α报告基因活性和mRNA水平，并表明HIPK 2在体内与HIF-1 α启动子结合，可能与组蛋白去乙酰化酶1（HDAC 1）形成多蛋白共阻遏物复合物。因此，在HIPK 2敲低后，HIF-1 α启动子被强烈乙酰化。通过共转染HIF-1 α的显性阴性（DN）构建体来评价HIF-1 α非依赖性VEGF转录，所述构建体抑制由HIPK 2敲低诱导的VEGF报告子活性。HIPK 2 i细胞中HIF-1 α和VEGF的上调与体内肿瘤异种移植物的血管分布增加和体外HUVEC中的管形成相关。这些发现提供了HIPK 2介导的HIF-1 α转录调节的第一个证据，HIF-1 α可能在VEGF表达中起关键作用。(c)2008 Elsevier B. V.保留所有权利。
HIPK2 has been implicated in restraining tumor progression by more than one mechanism, involving both its catalytic and transcriptional co-repressor functions. Starting from the finding that HIPK2 knockdown by RNA-interference (HIPK2i) induced significant up-regulation of HIF-1 alpha mRNA and of its target VEGF in tumor cells, we evaluated the role of HIPK2 in transcriptional regulation of HIF-1 alpha. We found that HIPK2 overexpression downmodulated both HIF-1 alpha reporter activity and mRNA levels and showed that HIPK2 was bound in vivo to the HIF-1 alpha promoter likely in a multiprotein co-repressor complex with histone deacetylase 1 (HDAC1). Thus, the HIF-1 alpha promoter was strongly acetylated following HIPK2 knockdown. The HIF-Independent VEGF transcription was evaluated by co-transfection of a dominant negative (DN) construct of HIF-1 alpha that inhibited VEGF reporter activity induced by HIPK2 knockdown. HIF-1 alpha and VEGF up-regulation in HIPK2i cells correlated with increased vascularity of tumor xenografts in vivo and tube formation in HUVEC in vitro. These findings provide the first evidence of HIPK2-mediated transcriptional regulation of HIF-1 alpha that might play a critical role in VEGF expression. (c) 2008 Elsevier B.V. All rights reserved.