Huang Xi, Zhang Mingyan, Pearce Alexander D, Gibbons Matthew D, Jin Dan, Li Lu, Hu Dongxin, Liu Renbin, Yu Mu, Tan Ming, Chang Jia, Dong Jixin, Xie Mingyi, Zhang Weizhou, Wu Lizi, Flores Catherine, Bungert Jörg, Brusko Todd M, Lu Jianrong
Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, China.
Cancers (Basel). 2025 Aug 25;17(17):2767. doi: 10.3390/cancers17172767.
: Epithelial-mesenchymal transition (EMT) is prevalent in human cancer and facilitates tumor metastasis and therapy resistance by enhancing cancer cell motility, invasiveness, survival, and immune evasion. However, the molecular mechanisms underlying the cellular changes during EMT remain largely elusive, making it challenging to simultaneously target these diverse malignant phenotypes. : Here, we show that the EMT-inducing ZEB transcription factors directly repressed WWC1 (also known as KIBRA), a key upstream activating component of the Hippo signaling pathway. The EMT program thus inherently downregulated WWC1, leading to impaired Hippo signaling and constitutive activation of the downstream effector and transcriptional coactivator YAP. The YAP-dependent transcriptional program promotes manifold cellular phenotypes that resemble those induced during EMT. Indeed, pharmacological inhibition of YAP suppressed EMT-stimulated cell migration and invasion, apoptosis resistance, and cell size growth, identifying active YAP as a common essential mediator of multiple EMT-associated phenotypes. Moreover, YAP activation directly induced transcription of B7 family immune checkpoint proteins VSIR (VISTA) and PD-L2, and rendered cancer cells resistant to effector CD8 T cells. : Collectively, the results suggest that EMT intrinsically activates YAP by repressing WWC1, providing a non-genetic mechanism for pervasive YAP activation in cancer. Activated YAP, in turn, critically contributes to diverse EMT-enhanced malignant phenotypes and immune evasion. Therefore, pharmacological targeting of YAP may suppress various EMT-associated malignant properties and improve the efficacy of anti-PD-1 immunotherapy, offering a promising therapeutic strategy against cancer cells exhibiting EMT characteristics.
上皮-间质转化（EMT）在人类癌症中普遍存在，通过增强癌细胞的运动性、侵袭性、生存能力和免疫逃逸促进肿瘤转移和治疗抗性。然而，EMT过程中细胞变化的分子机制仍 largely难以捉摸，这使得同时靶向这些不同的恶性表型具有挑战性。
在这里，我们表明，诱导EMT的ZEB转录因子直接抑制WWC1（也称为KIBRA），这是Hippo信号通路的关键上游激活成分。因此，EMT程序固有地下调WWC1，导致Hippo信号受损和下游效应器及转录共激活因子YAP的组成性激活。YAP依赖的转录程序促进多种细胞表型，类似于EMT期间诱导的表型。事实上，YAP的药理学抑制抑制了EMT刺激的细胞迁移和侵袭、凋亡抗性和细胞大小增长，确定活性YAP是多种EMT相关表型的共同必需介质。此外，YAP激活直接诱导B7家族免疫检查点蛋白VSIR（VISTA）和PD-L2的转录，并使癌细胞对效应CD8 T细胞产生抗性。
总的来说，结果表明EMT通过抑制WWC1内在地激活YAP，为癌症中普遍的YAP激活提供了一种非遗传机制。激活的YAP反过来又对多种EMT增强的恶性表型和免疫逃逸起关键作用。因此，YAP的药理学靶向可能抑制各种EMT相关的恶性特性并提高抗PD-1免疫疗法的疗效，为对抗表现出EMT特征的癌细胞提供了一种有前途的治疗策略。
