YAP and TAZ are central determinants of malignancy; however, their functions remain still undruggable. We identified TGFβ-activated kinase 1 (TAK1) as a central hub integrating the most relevant signals sustaining pancreatic cancer aggressiveness and chemoresistance. Glycogen synthase kinase (GSK)3 is known to stabilize TAK1, and its inhibition causes a reduction in TAK1 levels. Here, we hypothesized that TAK1 could sustain YAP/TAZ program, and thus, modulation of TAK1 expression through the inhibition of GSK3 could impair YAP/TAZ functions in pancreatic cancer. Differentially expressed transcripts between pancreatic cancer cells expressing scramble or TAK1-specific shRNA were annotated for functional interrelatedness by ingenuity pathway analysis. TAK1 expression was modulated by using different GSK3 inhibitors, including LY2090314. In vivo activity of LY2090314 alone or in combination with nab-paclitaxel was evaluated in an orthotopic nude mouse model. Differential gene expression profiling revealed significant association of TAK1 expression with HIPPO and ubiquitination pathways. We measured a significant downregulation of YAP/TAZ and their regulated genes in shTAK1 cells. TAK1 prevented YAP/TAZ proteasomal degradation in a kinase independent manner, through a complex with TRAF6, thereby fostering their K63-ubiquitination versus K48-ubiquitination. Pharmacologic modulation of TAK1 by using GSK3 inhibitors significantly decreased YAP/TAZ levels and suppressed their target genes and oncogenic functions. In vivo, LY2090314 plus nab-paclitaxel significantly prolonged mice survival duration. Our study demonstrates a unique role for TAK1 in controlling YAP/TAZ in pancreatic cancer. LY2090314 is a novel agent that warrants further clinical development in combination with nab-paclitaxel for the treatment of pancreatic cancer.

中文翻译：

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调节 TAK1 表达抑制胰腺癌中的 YAP 和 TAZ 致癌功能

YAP 和 TAZ 是恶性肿瘤的主要决定因素；然而，它们的功能仍然无法成药。我们将 TGFβ 活化激酶 1 (TAK1) 鉴定为整合维持胰腺癌侵袭性和化学抗性的最相关信号的中心枢纽。已知糖原合酶激酶 (GSK)3 可以稳定 TAK1，其抑制作用会导致 TAK1 水平降低。在这里，我们假设 TAK1 可以维持 YAP/TAZ 程序，因此，通过抑制 GSK3 来调节 TAK1 表达可能会损害 YAP/TAZ 在胰腺癌中的功能。通过独创性途径分析注释了表达 scramble 或 TAK1 特异性 shRNA 的胰腺癌细胞之间差异表达的转录本的功能相关性。TAK1 表达通过使用不同的 GSK3 抑制剂（包括 LY2090314）进行调节。在原位裸鼠模型中评估了 LY2090314 单独或与白蛋白结合型紫杉醇组合的体内活性。差异基因表达谱揭示了 TAK1 表达与 HIPPO 和泛素化途径的显着关联。我们测量了 shTAK1 细胞中 YAP/TAZ 及其调节基因的显着下调。TAK1 通过与 TRAF6 的复合物以激酶非依赖性方式阻止 YAP/TAZ 蛋白酶体降解，从而促进它们的 K63 泛素化与 K48 泛素化。通过使用 GSK3 抑制剂对 TAK1 的药理学调节显着降低了 YAP/TAZ 水平并抑制了它们的靶基因和致癌功能。在体内，LY2090314 加白蛋白结合型紫杉醇显着延长了小鼠的存活时间。我们的研究证明了 TAK1 在控制胰腺癌中的 YAP/TAZ 中的独特作用。LY2090314 是一种新型药物，值得进一步临床开发与白蛋白结合型紫杉醇联合用于治疗胰腺癌。