Cell type-dependent function of LATS1/2 in cancer cell growth
Cell type-dependent function of LATS1/2 in cancer cell growth
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DOI：
10.1038/s41388-018-0610-8
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发表时间：
2019-04-04
期刊：
影响因子：
8
通讯作者：
Guan, Kun-Liang
中科院分区：
文献类型：
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作者：
Pan, Wei-Wei;Moroishi, Toshiro;Guan, Kun-Liang
Hippo通路控制器官大小和组织稳态，其失调通常有助于肿瘤发生。广泛的研究表明，Hippo通路以细胞自主的方式抑制细胞增殖和存活。我们研究了Hippo途径激酶LATS 1/2（大肿瘤抑制因子1和2）在癌细胞中的功能。正如预期的那样，LATS 1/2的缺失促进大多数细胞系中的癌细胞生长。然而，令人惊讶的是，LATS 1/2缺失抑制鼠MC 38结肠癌细胞的生长，特别是在脱离条件下。LATS 1/2缺失引起的这种生长抑制作用是由于不受控制地激活了Yes相关蛋白（雅普）和具有PDZ结合基序的转录共激活因子（TAZ），这些转录共激活因子是LATS 1/2抑制的关键下游转录共激活因子。我们鉴定了Wnt诱导信号通路蛋白2（Wisp 2）和卷曲螺旋结构域80（Ccdc 80）作为雅普/TAZ的直接靶点。在MC 38细胞中，LATS 1/2缺失选择性诱导其表达。此外，WISP 2和CCDC 80的缺失防止了LATS 1/2缺失在MC 38细胞中的生长抑制作用。我们的研究表明，LATS 1/2在细胞生长中的功能是细胞环境依赖性的，这表明LATS 1/2抑制可以成为某些癌症类型的治疗方法。
The Hippo pathway controls organ size and tissue homeostasis, and its dysregulation often contributes to tumorigenesis. Extensive studies have shown that the Hippo pathway inhibits cell proliferation, and survival in a cell-autonomous manner. We examined the function of the Hippo pathway kinases LATS1/2 (large tumor suppressor 1 and 2) in cancer cells. As expected, loss of LATS1/2 promotes cancer cell growth in most cell lines. Surprisingly, however, LATS1/2 deletion inhibits the growth of murine MC38 colon cancer cells, especially under detachment conditions. This growth inhibitory effect caused by LATS1/2 deletion is due to uncontrolled activation of Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), the key downstream transcriptional coactivators inhibited by LATS1/2. We identified Wnt inducible signaling pathway protein 2 (Wisp2) and coiled-coil domain containing 80 (Ccdc80) as direct targets of YAP/TAZ. Their expression is selectively induced by LATS1/2 deletion in MC38 cells. Furthermore, deletion of WISP2 and CCDC80 prevents the growth inhibitory effect of LATS1/2 loss in MC38 cells. Our study demonstrates that the function of LATS1/2 in cell growth is cell context dependent, suggesting that LATS1/2 inhibition can be a therapeutic approach for some cancer types.