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首页> 外文期刊>Oncogene >Inverse PPARβ/δ agonists suppress oncogenic signaling to the ANGPTL4 gene and inhibit cancer cell invasion
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Inverse PPARβ/δ agonists suppress oncogenic signaling to the ANGPTL4 gene and inhibit cancer cell invasion

机译：逆pPARβ/δ激动剂抑制致癌信号传导到Angptl4基因并抑制癌细胞侵袭

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Besides its established functions in intermediary metabolism and developmental processes, the nuclear receptor peroxisome proliferator-activated receptor 尾/未 (PPAR尾/未) has a less defined role in tumorigenesis. In the present study, we have identified a function for PPAR尾/未 in cancer cell invasion. We show that two structurally divergent inhibitory ligands for PPAR尾/未, the inverse agonists ST247 and DG172, strongly inhibit the serum- and transforming growth factor 尾 (TGF尾)-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 PPAR尾/未 target in MDA-MB-231 cells, previously implicated in TGF尾-mediated tumor progression and metastatic dissemination. We show that the induction of ANGPTL4 by TGF尾 and other oncogenic signals is strongly repressed by ST247 and DG172 in a PPAR尾/未-dependent fashion, resulting in the inhibition of ANGPTL4 secretion. This effect is attributable to these ligands鈥?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 PPAR尾/未 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 PPAR尾/未鈥揂NGPTL4 pathway is involved in the regulation of tumor cell invasion and that its pharmacological manipulation by inverse PPAR尾/未 agonists is feasible.
机译：除了其中介代谢和发育过程中的既定功能，核受体过氧化物体增殖物激活受体△/未（PPAR尾/未）在肿瘤发生中具有较差的含义。在本研究中，我们已经确定了PPAR尾/Ⅳ在癌细胞侵袭中的功能。我们展示了PPAR尾/未的两个结构发散的抑制配体，反向激动剂ST247和DG172，强烈抑制血清和转化生长因子尾（TGF尾）诱导MDA-MB-231人乳腺癌细胞的侵袭到A中三维基质基质基质。为了阐明该发现的分子基础，我们进行了染色质免疫沉淀序列（Chip-SEQ）和微阵列分析，其鉴定了编码血管发成素的4（ AngptL4）的基因作为MDA的主要转录PPAR尾/未靶标的基因MB-231细胞，以前涉及TGF尾介质介导的肿瘤进展和转移传播。我们表明，通过T247和DG172在PPAR尾/未 - 依赖性时尚中强制抑制 Angpl4和其他致癌信号的诱导，导致Angptl4分泌的抑制。这种效果可归因于这些配体αααααααα诱导转录起始位点诱导显性转录阻遏物复合物的能力通过组蛋白脱乙酰化酶 - 无常规的非规范机制阻断过突出复合物。抑制 Angptl4通过反向PPAR = /未激动剂的转录在功能上与抑制癌细胞侵袭到三维基质中的抑制作用，因为（i）MDA-MB-231细胞的侵袭尺寸依赖于Angptl4表达， （ii）重组Angpt14刺激侵袭，（III）反转ST247和DG172的抑制作用。这些发现表明，PPAR尾/未揂NGPTL4途径涉及肿瘤细胞侵袭的调节，并通过逆PPAR尾/未激动剂的药理操纵是可行的。

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