Evading immune surveillance via tyrosine phosphorylation of nuclear PCNA
Yuan-Liang Wang,
Chuan-Chun Lee,
Yi-Chun Shen,
Pei-Le Lin,
Wan-Rong Wu,
You-Zhe Lin,
Wei-Chung Cheng,
Han Chang,
Yu Hung,
Yi-Chun Cho,
Liang-Chih Liu,
Wei-Ya Xia,
Jin-Huei Ji,
Ji-An Liang,
Shu-Fen Chiang,
Chang-Gong Liu,
Jun Yao,
Mien-Chie Hung,
Shao-Chun Wang
Affiliations
Yuan-Liang Wang
Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 40402, Taiwan
Chuan-Chun Lee
Center for Molecular Medicine, China Medical University Hospital, Taichung 40447, Taiwan
Yi-Chun Shen
Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 40402, Taiwan
Pei-Le Lin
Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 40402, Taiwan
Wan-Rong Wu
Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 40402, Taiwan
You-Zhe Lin
Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 40402, Taiwan
Wei-Chung Cheng
Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 40402, Taiwan; Research Center for Tumor Medical Science, China Medical University, Taichung 40402, Taiwan; Cancer Biology and Drug Discovery Ph.D. Program, China Medical University, Taichung 40402, Taiwan
Han Chang
Division of Molecular Pathology, Department of Pathology, China Medical University Hospital, Taichung 40447, Taiwan
Yu Hung
Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 40402, Taiwan
Yi-Chun Cho
Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 40402, Taiwan
Liang-Chih Liu
Department of Surgery, China Medical University Hospital, Taichung 40447, Taiwan
Wei-Ya Xia
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Jin-Huei Ji
Department of Radiation Oncology, China Medical University Hospital, Taichung 40447, Taiwan
Ji-An Liang
School of Medicine, College of Medicine, China Medical University, Taichung 40402, Taiwan; Department of Radiation Oncology, China Medical University Hospital, Taichung 40447, Taiwan
Shu-Fen Chiang
Lab of Precision Medicine, Feng-Yuan Hospital, Ministry of Health and Welfare, Taichung, Taiwan
Chang-Gong Liu
Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA
Jun Yao
Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Mien-Chie Hung
Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 40402, Taiwan; Center for Molecular Medicine, China Medical University Hospital, Taichung 40447, Taiwan; Research Center for Tumor Medical Science, China Medical University, Taichung 40402, Taiwan; Drug Development Center, China Medical University, Taichung 40402, Taiwan; Cancer Biology and Drug Discovery Ph.D. Program, China Medical University, Taichung 40402, Taiwan; Department of Biotechnology, Asia University, Taichung 41354, Taiwan; Corresponding author
Shao-Chun Wang
Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 40402, Taiwan; Center for Molecular Medicine, China Medical University Hospital, Taichung 40447, Taiwan; Research Center for Tumor Medical Science, China Medical University, Taichung 40402, Taiwan; Drug Development Center, China Medical University, Taichung 40402, Taiwan; Cancer Biology and Drug Discovery Ph.D. Program, China Medical University, Taichung 40402, Taiwan; Department of Biotechnology, Asia University, Taichung 41354, Taiwan; Department of Cancer Biology, University of Cincinnati, Cincinnati, OH 45267, USA; Corresponding author
Summary: Increased DNA replication and metastasis are hallmarks of cancer progression, while deregulated proliferation often triggers sustained replication stresses in cancer cells. How cancer cells overcome the growth stress and proceed to metastasis remains largely elusive. Proliferating cell nuclear antigen (PCNA) is an indispensable component of the DNA replication machinery. Here, we show that phosphorylation of PCNA on tyrosine 211 (pY211-PCNA) regulates DNA metabolism and tumor microenvironment. Abrogation of pY211-PCNA blocks fork processivity, resulting in biogenesis of single-stranded DNA (ssDNA) through a MRE11-dependent mechanism. The cytosolic ssDNA subsequently induces inflammatory cytokines through a cyclic GMP-AMP synthetase (cGAS)-dependent cascade, triggering an anti-tumor immunity by natural killer (NK) cells to suppress distant metastasis. Expression of pY211-PCNA is inversely correlated with cytosolic ssDNA and associated with poor survival in patients with cancer. Our results pave the way to biomarkers and therapies exploiting immune responsiveness to target metastatic cancer.
