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

doi:10.1016/j.celrep.2021.109537

Evading immune surveillance via tyrosine phosphorylation of nuclear PCNA

Cell Rep. 2021 Aug 24;36(8):109537. doi: 10.1016/j.celrep.2021.109537.

Authors

Yuan-Liang Wang¹, Chuan-Chun Lee², Yi-Chun Shen¹, Pei-Le Lin¹, Wan-Rong Wu¹, You-Zhe Lin¹, Wei-Chung Cheng³, Han Chang⁴, Yu Hung¹, Yi-Chun Cho¹, Liang-Chih Liu⁵, Wei-Ya Xia⁶, Jin-Huei Ji⁷, Ji-An Liang⁸, Shu-Fen Chiang⁹, Chang-Gong Liu¹⁰, Jun Yao¹¹, Mien-Chie Hung¹², Shao-Chun Wang¹³

Affiliations

¹ Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 40402, Taiwan.
² Center for Molecular Medicine, China Medical University Hospital, Taichung 40447, Taiwan.
³ 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.
⁴ Division of Molecular Pathology, Department of Pathology, China Medical University Hospital, Taichung 40447, Taiwan.
⁵ Department of Surgery, China Medical University Hospital, Taichung 40447, Taiwan.
⁶ Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁷ Department of Radiation Oncology, China Medical University Hospital, Taichung 40447, Taiwan.
⁸ School of Medicine, College of Medicine, China Medical University, Taichung 40402, Taiwan; Department of Radiation Oncology, China Medical University Hospital, Taichung 40447, Taiwan.
⁹ Lab of Precision Medicine, Feng-Yuan Hospital, Ministry of Health and Welfare, Taichung, Taiwan.
¹⁰ Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
¹¹ Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹² 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. Electronic address: mhung@cmu.edu.tw.
¹³ 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. Electronic address: scpwang@mail.cmu.edu.tw.

PMID: 34433039
DOI: 10.1016/j.celrep.2021.109537

Abstract

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.

Keywords: PCNA; cGAS; innate immune response; pY211 PCNA; ssDNA; type I interferon.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Female
Humans
MCF-7 Cells
Mice
Mice, Transgenic
Neoplasms, Experimental / genetics
Neoplasms, Experimental / immunology*
Neoplasms, Experimental / mortality
Phosphorylation
Proliferating Cell Nuclear Antigen / genetics
Proliferating Cell Nuclear Antigen / immunology*
Tumor Escape*
Tumor Microenvironment / genetics
Tumor Microenvironment / immunology*
Tyrosine / genetics
Tyrosine / immunology

Substances

PCNA protein, human
Proliferating Cell Nuclear Antigen
Tyrosine