Hip to the Game: YAP/TAZ is required for nonmelanoma skin cancers

Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the two most common skin cancers found in humans. These cancers can acquire drug resistance and pose considerable medical burdens to clinics and patients if left untreated. Two recent studies show that active Hippo signaling plays a critical role in initiating BCC and SCC tumorigenesis, providing new opportunities to develop therapies against these skin malignancies.     

Tolfenamic acid negatively regulates YAP and TAZ expression in human cancer cells

Several diseases are associated with improper regulation of the Hippo pathway, which plays an important role in cell proliferation and cancer metastasis. Overactivation of the YAP and TAZ proteins accelerates cell proliferation, invasion, and migration during tumorigenesis. Tolfenamic acid (TA) is a non-steroidal anti-inflammatory drug (NSAID) that exhibits activity against various types of cancer. In this study, we observed that TA decreased YAP and TAZ protein levels in cancer cells. TA increased the phosphorylation of YAP and TAZ, leading to the degradation of YAP and TAZ in the cytoplasm and nucleus. TA predominantly affected multiple phosphodegron sites in the YAP and TAZ and lowered 14-3-3β protein expression, causing YAP and TAZ to enter the ubiquitination pathway. Proteins that affect YAP and TAZ regulation, such as NAG-1 and several YAP/TAZ E3 ligases, were not involved in TA-mediated YAP/TAZ degradation. In summary, our results indicate that TA affects phosphodegron sites on YAP/TAZ, demonstrating a novel effect of TA in tumorigenesis.     

Colonic epithelium rejuvenation through YAP/TAZ

Stem cells are critical for normal tissue homeostasis and injury‐induced regeneration, but how wounding affects tissue regeneration at the cellular and molecular levels is not yet fully understood. A new study by Yui et al ( 2018 ) demonstrates that the extracellular matrix (ECM) remodeling modulates intestinal stem cells in tissue repair and regeneration via activation of the Hippo pathway effectors YAP/TAZ.     

ECM和YAP/TAZ在决定细胞命运的过程中的作用机制

近年来,有研究表表明从细胞微环境中转化而来的机械信号可以调控细胞形状和影响细胞的命运。然而,这些机械信号转化成调节细胞生物过程的信号的机制仍然不是十分清楚。最新研究已阐明细胞可通过来自细胞外基质(extracellular matrix,ECM)的机械信号和细胞行为调控之间的相互作用来募集Hippo信号通路中的核心组件YAP/TAZ的作用机制。此外,研究发现在Wnt和Hippo信号之间的串扰是调节细胞命运的核心。这些机制可以解释力学微环境的信号是如何调节细胞行为和决定细胞命运的。本文重点对ECM和YAP/TAZ在决定细胞命运的过程中的作用机制展开系统综述。     

Glucose dysregulation promotes oncogenesis in human bladder cancer by regulating autophagy and YAP1/TAZ expression

Glucose dysregulation is strongly correlated with cancer development, and cancer is prevalent in patients with Type 2 diabetes (T2D). We aimed to elucidate the mechanism underlying autophagy in response to glucose dysregulation in human bladder cancer (BC). 220 BC patients were included in this retrospective study. The expression of YAP1, TAZ and AMPK, EMT-associated markers, and autophagy marker proteins was analysed by immunohistochemistry, western blotting, and quantitative real-time PCR (qPCR). Further, T24 and UMUC-3 BC cells were cultured in media with different glucose concentrations, and the expression of YAP1, TAZ, AMPK and EMT-associated markers, and autophagy marker proteins was analysed by western blotting and qPCR. Autophagy was observed by immunofluorescence and electron microscopy. BC cell viability was tested using MTT assays. A xenograft nude mouse model of diabetes was used to evaluate tumour growth, metastasis and survival. A poorer pathologic grade and tumour-node-metastasis stage were observed in patients with BC with comorbid T2D than in others with BC. YAP1 and TAZ were upregulated in BC samples from patients with T2D. Mechanistically, high glucose (HG) promoted BC progression both in vitro and in vivo and inhibited autophagy. Specifically, various autophagy marker proteins and AMPK were negatively regulated under HG conditions and correlated with YAP1 and TAZ expression. These results demonstrate that HG inhibits autophagy and promotes cancer development in BC. YAP1/TAZ/AMPK signalling plays a crucial role in regulating glucose dysregulation during autophagy. Targeting these effectors exhibits therapeutic significance and can serve as prognostic markers in BC patients with T2D.