YTHDF2-mediated circYAP1 drives immune escape and cancer progression through activating YAP1/TCF4-PD-L1 axis

Zhuang Chen; Wenkang Wang; Shengyun Hu; Haifeng Sun; Chen Chen; Zhiyong Zhang; Xinzhi Sun; Bin Jia; Junhong Hu; Chengzeng Wang; Yang Liu; Zhenqiang Sun

doi:10.1016/j.isci.2023.108779

YTHDF2-mediated circYAP1 drives immune escape and cancer progression through activating YAP1/TCF4-PD-L1 axis

iScience. 2023 Dec 30;27(2):108779. doi: 10.1016/j.isci.2023.108779. eCollection 2024 Feb 16.

Authors

Zhuang Chen^{1

2}, Wenkang Wang³, Shengyun Hu¹, Haifeng Sun¹, Chen Chen², Zhiyong Zhang¹, Xinzhi Sun⁴, Bin Jia⁵, Junhong Hu¹, Chengzeng Wang^{2

6}, Yang Liu⁷, Zhenqiang Sun^{1

2}

Affiliations

¹ Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.
² Henan Institute of Interconnected Intelligent Health Management, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.
³ Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.
⁴ Department of Orthopaedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.
⁵ Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.
⁶ Department of Ultrasound, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.
⁷ Department of Radiotherapy, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China.

Abstract

Immune escape is identified as one of the reasons for the poor prognosis of colorectal cancer (CRC) patients. Circular RNAs are considered to promote tumor progression by mediating tumor immune escape. We discovered that higher expression of circYAP1 was associated with a worse prognosis of CRC patients. Functional experiments in vitro and in vivo showed that circYAP1 upregulation inhibited the cytotoxicity of CD8⁺ T cells by upregulating programmed death ligand-1 (PD-L1). Mechanistically, we found that circYAP1 directly binds to the YAP1 protein to prevent its phosphorylation, enhancing proportion of YAP1 protein in the nucleus, and that YAP1 interacts with TCF4 to target the PD-L1 promoter and initiate PD-L1 transcription in CRC cells. Taken together, circYAP1 promotes CRC immune escape and tumor progression by activating the YAP1/TCF4-PD-L1 axis and may provide a new strategy for combination immunotherapy of CRC patients.

Keywords: Cancer; Cell biology; Immunology; Molecular biology.