Pancreatic ductal adenocarcinoma (PDAC) is the most lethal malignancy in humans, and new therapeutic targets are urgently needed. Yes-associated protein (YAP) plays a significant role in cancer progression. Autophagy is also closely associated with various human cancers. However, the interplay between YAP and autophagy in PDAC remains poorly understood. In this study, we found that YAP was upregulated and activated in PDAC. Further analysis revealed that there is a YAP-autophagy feedback loop in pancreatic cancer. Mechanistically, YAP activates autophagy by promoting Atg5 transcription via TEAD1-mediated binding, while autophagy negatively regulates YAP through autophagic degradation. The hyperactivation of YAP in PDAC unbalances the YAP-autophagy circuit and promotes cancer progression. Inhibition of autophagy enhances the oncogenic activity of YAP in PDAC. The autophagy activator rapamycin promotes the antitumor effect of verteporfin, a YAP inhibitor. Therefore, our study elucidated the interaction between YAP and autophagy in PDAC and our results suggest that targeting the YAP-autophagy circuit may be a new therapeutic strategy for pancreatic cancer.

中文翻译：

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自噬介导的负反馈减弱 YAP 在胰腺癌中的致癌活性


胰腺导管腺癌（PDAC）是人类最致命的恶性肿瘤，迫切需要新的治疗靶点。 Yes相关蛋白（YAP）在癌症进展中发挥着重要作用。自噬也与多种人类癌症密切相关。然而，YAP 和 PDAC 自噬之间的相互作用仍然知之甚少。在这项研究中，我们发现 YAP 在 PDAC 中上调并被激活。进一步分析表明，胰腺癌中存在YAP-自噬反馈环。从机制上讲，YAP 通过 TEAD1 介导的结合促进 Atg5 转录来激活自噬，而自噬则通过自噬降解负向调节 YAP。 PDAC 中 YAP 的过度激活会破坏 YAP 自噬回路的平衡并促进癌症进展。自噬的抑制增强了 PDAC 中 YAP 的致癌活性。自噬激活剂雷帕霉素可促进 YAP 抑制剂维替泊芬的抗肿瘤作用。因此，我们的研究阐明了 PDAC 中 YAP 与自噬之间的相互作用，我们的结果表明，靶向 YAP-自噬回路可能是胰腺癌的一种新治疗策略。