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首页> 外文期刊>Oncogene >Inverse PPAR|[beta]||[sol]||[delta]| agonists suppress oncogenic signaling to the ANGPTL4 gene and inhibit cancer cell invasion
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Inverse PPAR|[beta]||[sol]||[delta]| agonists suppress oncogenic signaling to the ANGPTL4 gene and inhibit cancer cell invasion

机译：逆PPAR |β|| [sol] ||δ|激动剂抑制向ANGPTL4基因致癌的信号传导并抑制癌细胞侵袭

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Besides its established functions in intermediary metabolism and developmental processes, the nuclear receptor peroxisome proliferator-activated receptor β/δ (PPARβ/δ) has a less defined role in tumorigenesis. In the present study, we have identified a function for PPARβ/δ in cancer cell invasion. We show that two structurally divergent inhibitory ligands for PPARβ/δ, the inverse agonists ST247 and DG172, strongly inhibit the serum- and transforming growth factor β (TGFβ)-induced invasion of MDA-MB-231 human breast cancer cells into a three-dimensional matrigel matrix. To elucidate the molecular basis of this finding, we performed chromatin immunoprecipitation sequencing (ChIP-Seq) and microarray analyses, which identified the gene encoding angiopoietin-like 4 (ANGPTL4) as the major transcriptional PPARβ/δ target in MDA-MB-231 cells, previously implicated in TGFβ-mediated tumor progression and metastatic dissemination. We show that the induction of ANGPTL4 by TGFβ and other oncogenic signals is strongly repressed by ST247 and DG172 in a PPARβ/δ-dependent fashion, resulting in the inhibition of ANGPTL4 secretion. This effect is attributable to these ligands’ ability to induce a dominant transcriptional repressor complex at the site of transcription initiation that blocks preinitiation complex formation through an histone deacetylase-independent, non-canonical mechanism. Repression of ANGPTL4 transcription by inverse PPARβ/δ agonists is functionally linked to the inhibition of cancer cell invasion into a three-dimensional matrix, as (i) invasion of MDA-MB-231 cells is critically dependent on ANGPTL4 expression, (ii) recombinant ANGPTL4 stimulates invasion, and (iii) reverses the inhibitory effect of ST247 and DG172. These findings indicate that a PPARβ/δ–ANGPTL4 pathway is involved in the regulation of tumor cell invasion and that its pharmacological manipulation by inverse PPARβ/δ agonists is feasible.
机译：除了在中间代谢和发育过程中确立的功能外，核受体过氧化物酶体增殖物激活的受体β/δ（PPARβ/δ）在肿瘤发生中的作用还不太明确。在本研究中，我们已经确定了PPARβ/δ在癌细胞侵袭中的功能。我们显示，PPARβ/δ的两个结构不同的抑制性配体，即反向激动剂ST247和DG172，强烈抑制了血清和转化生长因子β（TGFβ）诱导的MDA-MB-231人乳腺癌细胞向三细胞侵袭。维矩阵矩阵。为了阐明该发现的分子基础，我们进行了染色质免疫沉淀测序（ChIP-Seq）和微阵列分析，确定了编码血管生成素样4（ANGPTL4）的基因是MDA-MB-231细胞中主要的转录PPARβ/δ靶标。 ，以前与TGFβ介导的肿瘤进展和转移性传播有关。我们表明，TGFβ和其他致癌信号对ANGPTL4的诱导被ST247和DG172强烈抑制，呈PPARβ/δ依赖性，从而抑制了ANGPTL4的分泌。这种作用可归因于这些配体在转录起始位点诱导显性转录阻遏物复合物的能力，该结构可通过组蛋白脱乙酰基酶非依赖性非常规机制阻止预起始复合物的形成。通过反向PPARβ/δ激动剂抑制ANGPTL4转录在功能上与抑制癌细胞入侵三维矩阵有关，因为（i）MDA-MB-231细胞的入侵严重依赖于ANGPTL4表达，（ii）重组ANGPTL4刺激侵袭，并且（iii）逆转ST247和DG172的抑制作用。这些发现表明，PPARβ/δ-ANGPTL4通路参与肿瘤细胞侵袭的调节，并且通过逆PPARβ/δ激动剂对其进行药理操作是可行的。

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