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
Affiliations
Zhuang Chen
Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Henan Institute of Interconnected Intelligent Health Management, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
Wenkang Wang
Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
Shengyun Hu
Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
Haifeng Sun
Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
Chen Chen
Henan Institute of Interconnected Intelligent Health Management, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
Zhiyong Zhang
Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
Xinzhi Sun
Department of Orthopaedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
Bin Jia
Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
Junhong Hu
Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
Chengzeng Wang
Henan Institute of Interconnected Intelligent Health Management, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Department of Ultrasound, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Corresponding author
Yang Liu
Department of Radiotherapy, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China; Corresponding author
Zhenqiang Sun
Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Henan Institute of Interconnected Intelligent Health Management, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Corresponding author
Summary: 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.
