Tim Hon Man Chan1, Aditi Qamra2, Kar Tong Tan1, Jing Guo1, Henry Yang1, Lihua Qi1, Jaymie Siqi Lin1, Vanessa Hui En Ng1, Yangyang Song1, Huiqi Hong1, Su Ting Tay3, Yujing Liu4, Jeeyun Lee5, Sun Yong Rha6, Feng Zhu7, Jimmy Bok Yan So7, Bin Tean Teh8, Khay Guan Yeoh9, Steve Rozen10, Daniel G Tenen11, Patrick Tan12, Leilei Chen13. 1. Cancer Science Institute of Singapore, National University of Singapore, Singapore. 2. Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. 3. Cancer and Stem Cell Biology Program, Duke-National University of Singapore Graduate Medical School, Singapore. 4. Cancer and Stem Cell Biology Program, Duke-National University of Singapore Graduate Medical School, Singapore; Singapore-Massachusetts Institute of Technology Alliance, Singapore. 5. Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. 6. Yonsei Cancer Center, Seodaemun-gu, Seoul, South Korea. 7. Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. 8. Cancer Science Institute of Singapore, National University of Singapore, Singapore; Cancer and Stem Cell Biology Program, Duke-National University of Singapore Graduate Medical School, Singapore; Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore. 9. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Department of Gastroenterology and Hepatology, National University Health System, Singapore. 10. Cancer and Stem Cell Biology Program, Duke-National University of Singapore Graduate Medical School, Singapore; Centre for Computational Biology, Duke-National University of Singapore Graduate Medical School, Singapore. 11. Cancer Science Institute of Singapore, National University of Singapore, Singapore; Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts. 12. Cancer Science Institute of Singapore, National University of Singapore, Singapore; Cancer and Stem Cell Biology Program, Duke-National University of Singapore Graduate Medical School, Singapore; Cellular and Molecular Research, National Cancer Centre, Singapore; Genome Institute of Singapore, Singapore. Electronic address: gmstanp@duke-nus.edu.sg. 13. Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Electronic address: csicl@nus.edu.sg.
Abstract
BACKGROUD & AIMS: Gastric cancer (GC) is the third leading cause of global cancer mortality. Adenosine-to-inosine RNA editing is a recently described novel epigenetic mechanism involving sequence alterations at the RNA but not DNA level, primarily mediated by ADAR (adenosine deaminase that act on RNA) enzymes. Emerging evidence suggests a role for RNA editing and ADARs in cancer, however, the relationship between RNA editing and GC development and progression remains unknown. METHODS: In this study, we leveraged on the next-generation sequencing transcriptomics to demarcate the GC RNA editing landscape and the role of ADARs in this deadly malignancy. RESULTS: Relative to normal gastric tissues, almost all GCs displayed a clear RNA misediting phenotype with ADAR1/2 dysregulation arising from the genomic gain and loss of the ADAR1 and ADAR2 gene in primary GCs, respectively. Clinically, patients with GCs exhibiting ADAR1/2 imbalance demonstrated extremely poor prognoses in multiple independent cohorts. Functionally, we demonstrate in vitro and in vivo that ADAR-mediated RNA misediting is closely associated with GC pathogenesis, with ADAR1 and ADAR2 playing reciprocal oncogenic and tumor suppressive roles through their catalytic deaminase domains, respectively. Using an exemplary target gene PODXL (podocalyxin-like), we demonstrate that the ADAR2-regulated recoding editing at codon 241 (His to Arg) confers a loss-of-function phenotype that neutralizes the tumorigenic ability of the unedited PODXL. CONCLUSIONS: Our study highlights a major role for RNA editing in GC disease and progression, an observation potentially missed by previous next-generation sequencing analyses of GC focused on DNA alterations alone. Our findings also suggest new GC therapeutic opportunities through ADAR1 enzymatic inhibition or the potential restoration of ADAR2 activity.
BACKGROUD & AIMS: Gastric cancer (GC) is the third leading cause of global cancermortality. Adenosine-to-inosine RNA editing is a recently described novel epigenetic mechanism involving sequence alterations at the RNA but not DNA level, primarily mediated by ADAR (adenosine deaminase that act on RNA) enzymes. Emerging evidence suggests a role for RNA editing and ADARs in cancer, however, the relationship between RNA editing and GC development and progression remains unknown. METHODS: In this study, we leveraged on the next-generation sequencing transcriptomics to demarcate the GC RNA editing landscape and the role of ADARs in this deadly malignancy. RESULTS: Relative to normal gastric tissues, almost all GCs displayed a clear RNA misediting phenotype with ADAR1/2 dysregulation arising from the genomic gain and loss of the ADAR1 and ADAR2 gene in primary GCs, respectively. Clinically, patients with GCs exhibiting ADAR1/2 imbalance demonstrated extremely poor prognoses in multiple independent cohorts. Functionally, we demonstrate in vitro and in vivo that ADAR-mediated RNA misediting is closely associated with GC pathogenesis, with ADAR1 and ADAR2 playing reciprocal oncogenic and tumor suppressive roles through their catalytic deaminase domains, respectively. Using an exemplary target gene PODXL (podocalyxin-like), we demonstrate that the ADAR2-regulated recoding editing at codon 241 (His to Arg) confers a loss-of-function phenotype that neutralizes the tumorigenic ability of the unedited PODXL. CONCLUSIONS: Our study highlights a major role for RNA editing in GC disease and progression, an observation potentially missed by previous next-generation sequencing analyses of GC focused on DNA alterations alone. Our findings also suggest new GC therapeutic opportunities through ADAR1 enzymatic inhibition or the potential restoration of ADAR2 activity.
Authors: Xinxin Peng; Xiaoyan Xu; Yumeng Wang; David H Hawke; Shuangxing Yu; Leng Han; Zhicheng Zhou; Kamalika Mojumdar; Kang Jin Jeong; Marilyne Labrie; Yiu Huen Tsang; Minying Zhang; Yiling Lu; Patrick Hwu; Kenneth L Scott; Han Liang; Gordon B Mills Journal: Cancer Cell Date: 2018-04-26 Impact factor: 31.743