Activation of Aurora A kinase increases YAP stability via blockage of autophagy

Peng Wang,Muhammad Kamran,Chundong Gu,Mie-Chie Hung,Fei Peng,Lei Fang,Qimin Zhan,Chunli Wang,Xiaoyuan Xue,Tao Guo,Man Li,Jie Xu,Shengchen Yin,Quentin Liu,Eric W.-F Lam,Lingzhi Xu,Yang Liu,Ying Gong,Mengying Yang

doi:10.1038/s41419-019-1664-4

Abstract

Transcription cofactor Yes-associated protein (YAP) plays an important role in cancer progression. Here, we found that Aurora A kinase expression was positively correlated with YAP in lung cancer. Aurora A depletion suppresses lung cancer cell colony formation, which could be reversed by YAP ectopic overexpression. In addition, activation of Aurora A increases YAP protein abundance through maintaining its protein stability. Consistently, the transcriptional activity of YAP is increased upon Aurora A activation. We further showed that shAURKA suppressed YAP expression in the absence of Lats1/2, indicating that Aurora A regulates YAP independently of Hippo pathway. Instead, Aurora A induced blockage of autophagy to up-regulate YAP expression. Collectively, our findings provide insights into regulatory mechanisms of YAP expression in lung cancer development.

Highlights

Introduction TheHippo pathway functions as a key regulator of cell proliferation and organ size[1]
The statistical analysis revealed a positive correlation between Aurora A and Yes-associated protein (YAP) protein expression (R2 = 0.8720, p < 0.001) (Fig. 1a, right panel), indicating that YAP overexpression is associated with high Aurora A levels in clinical lung cancer tissues
Of 43 patients, 33(76.7%) tissue specimens showed simultaneously high-expression or low-expression of Aurora A and YAP, indicating that YAP expression levels are positively correlated with Aurora A in lung cancer

Summary

Introduction

Hippo pathway functions as a key regulator of cell proliferation and organ size[1]. As the core component of Hippo pathway, the Yes-associated protein (YAP) shuttles between the cytoplasm and nucleus. YAP interacts with DNA-binding transcription factors TEAD to promote the expression of several growth-related genes, including CTGF and CYR612,3. The cellular location of YAP is determined by its phosphorylation status which is mainly regulated by upstream kinases in Hippo pathway[4,5,6,7]. Dysregulation of Hippo pathway exerts a significant impact on the development of a number of cancers, including lung cancer[14], colorectal cancer[15], ovarian cancer[16] and liver cancer[17]

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Results

Conclusion