A comprehensive evaluation of Hippo pathway silencing in sarcomas.
A comprehensive evaluation of Hippo pathway silencing in sarcomas.
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DOI：
10.18632/oncotarget.25824
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发表时间：
2018-08-03
期刊：
影响因子：
--
通讯作者：
Tanas MR
中科院分区：
文献类型：
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作者：
Merritt NM;Fullenkamp CA;Hall SL;Qian Q;Desai C;Thomason J;Lambertz AM;Dupuy AJ;Darbro B;Tanas MR
TAZ和YAP是受Hippo通路负调控的转录共激活因子，在包括肉瘤在内的几种癌症中已成为关键的癌蛋白。我们假设Hippo激酶的表达缺失可能是激活TAZ和YAP的一种机制。通过免疫组化，TAZ/YAP激活的临床肉瘤样品显示MST1 (47%), MST2 (26%), LATS1（19%）和LATS2（27%）的丢失。Western blot同样显示MST1（58%）、MST2（25%）和LATS2（17%）的缺失。MG132在25%的肉瘤细胞系中积累了MST2，这表明蛋白体降解调节了MST2的表达。在肉瘤细胞系中，qRT-PCR显示在RNA水平上Hippo激酶的表达缺失，在MST1（42%）和MST2（25%）中最明显。5-氮杂胞苷在肉瘤细胞系中适度逆转MST1（8%）和MST2（17%）的表达，表明CpG岛超甲基化可以沉默MST1和MST2的表达。Trichostatin A处理逆转了MST1（58%）和MST2（67%）的表达，表明组蛋白去乙酰化也在沉默MST1和MST2的表达中起作用。Hippo激酶的表达缺失在肉瘤中很常见，这是由于多种机制，包括翻译后水平的调控和表观遗传沉默。
TAZ and YAP are transcriptional coactivators negatively regulated by the Hippo pathway that have emerged as key oncoproteins in several cancers including sarcomas. We hypothesized that loss of expression of the Hippo kinases might be a mechanism of activating TAZ and YAP. By immunohistochemistry, TAZ/YAP activated clinical sarcoma samples demonstrated loss of MST1 (47%), MST2 (26%), LATS1 (19%), and LATS2 (27%). Western blot similarly demonstrated loss of MST1 (58%), MST2 (25%), and LATS2 (17%). Treatment with MG132 demonstrated an accumulation of MST2 in 25% of sarcoma cell lines, indicating that proteosomal degradation regulates MST2 expression. qRT-PCR in sarcoma cell lines demonstrated loss of expression of the Hippo kinases at the RNA level, most pronounced in MST1 (42%) and MST2 (25%). 5-azacytidine treatment in sarcoma cell lines modestly reversed expression of predominantly MST1 (8%) and MST2 (17%), indicating CpG island hypermethylation can silence expression of MST1 and MST2. Trichostatin A treatment reversed expression of MST1 (58%) and MST2 (67%), indicating histone deacetylation also plays a role in silencing expression of MST1 and MST2. Loss of expression of the Hippo kinases is frequent in sarcomas and is due to a variety of mechanisms including regulation at the post-translational level and epigenetic silencing.