YAP1 plays a key role of the conversion of normal fibroblasts into cancer-associated fibroblasts that contribute to prostate cancer progression

Tianyu Shen,Jianpeng Yu,Shimiao Zhu,Yuanjie Niu,Zheng Zhang,Xuanrong Chen,Yuan Ma,Yang Li,Boya Zhang,Zhiqun Shang

doi:10.1186/s13046-020-1542-z

Abstract

BackgroundCancer-associated fibroblasts (CAFs) are an important part of the tumour microenvironment, and their functions are of great concern. This series of experiments aimed to explore how Yes-associated protein 1 (YAP1) regulates the function of stromal cells and how the normal fibroblasts (NFs) convert into CAFs in prostate cancer (PCa).MethodsThe effects of conditioned media from different fibroblasts on the proliferation and invasion of epithelial cells TrampC1 were examined. We then analysed the interaction between the YAP1/TEAD1 protein complex and SRC, as well as the regulatory function of the downstream cytoskeletal proteins and actins. A transplanted tumour model was used to explore the function of YAP1 in regulating tumour growth through stromal cells. The relationship between the expression of YAP1 in tumour stromal cells and the clinical characteristics of PCa patients was analysed.ResultsThe expression level of YAP1 was significantly upregulated in PCa stromal cells. After the expression level of YAP1 was increased, NF was transformed into CAF, enhancing the proliferation and invasion ability of epithelial cells. The YAP1/TEAD1 protein complex had the capability to influence downstream cytoskeletal proteins by regulating SRC transcription; therefore, it converts NF to CAF, and CAF can significantly promote tumour growth and metastasis. The high expression of YAP1 in the tumour stromal cells suggested a poor tumour stage and prognosis in PCa patients.ConclusionYAP1 can convert NFs into CAFs in the tumour microenvironment of PCa, thus promoting the development and metastasis of PCa. Silencing YAP1 in tumour stromal cells can effectively inhibit tumour growth.

Highlights

Cancer-associated fibroblasts (CAFs) are an important part of the tumour microenvironment, and their functions are of great concern
We used siYAP1 and the inhibitor verteporfin (VP) to reduce the activity of Yes-associated protein 1 (YAP1) in CAFs (Supplementary Figure S2A-B), and we found that the proliferation ability of the CAFs was significantly inhibited (Supplementary Figure S2C-D) and that when the YAP1 level was raised in the Normal fibroblast (NF) (Supplementary Figure S2E), their proliferation ability was significantly enhanced (Supplementary Figure S2F)
YAP1/TEA domain transcription factor 1 (TEAD1) protein complex activates cytoskeletal proteins to transform NFs to CAFs by regulating SRC proto-oncogene (SRC) We have proved that YAP1 was associated with the conversion of NFs into CAFs, but its mechanism remains unclear

Summary

Introduction

Cancer-associated fibroblasts (CAFs) are an important part of the tumour microenvironment, and their functions are of great concern. This series of experiments aimed to explore how Yes-associated protein 1 (YAP1) regulates the function of stromal cells and how the normal fibroblasts (NFs) convert into CAFs in prostate cancer (PCa). The Hippo signalling pathway plays an important role in the development of prostate cancer [2,3,4,5]. The Hippo signalling pathway contains 13 core proteins including MST1 / 2, SAV1, LATS1 / 2, MOB1A, MOB1B, YAP1, TAZ and TEAD1–4 [6]. YAP1 acts as a downstream transcriptional coactivator of the Hippo pathway. Since YAP1 is active in cancer cells, it can regulate a variety of cancer genes or form complexes with them and jointly regulate the downstream target genes

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