School of Life Science and Technology, ShanghaiTech University, Shanghai 201203, China; Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China
Tao Wu
School of Life Science and Technology, ShanghaiTech University, Shanghai 201203, China; Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China
Shixiang Wang
School of Life Science and Technology, ShanghaiTech University, Shanghai 201203, China; Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China
Jing Zhang
School of Life Science and Technology, ShanghaiTech University, Shanghai 201203, China; Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China
Xiaoqin Sun
School of Life Science and Technology, ShanghaiTech University, Shanghai 201203, China
Ziyu Tao
School of Life Science and Technology, ShanghaiTech University, Shanghai 201203, China
Xiangyu Zhao
School of Life Science and Technology, ShanghaiTech University, Shanghai 201203, China
Huimin Li
School of Life Science and Technology, ShanghaiTech University, Shanghai 201203, China
Kai Wu
Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
Xue-Song Liu
School of Life Science and Technology, ShanghaiTech University, Shanghai 201203, China; Corresponding author
Summary: Noncoding DNA sequences occupy more than 98% of the human genome; however, few cancer noncoding drivers have been identified compared with cancer coding drivers, probably because cancer noncoding drivers have a distinct mutation pattern due to the distinct function of noncoding DNA. Here we performed pan-cancer whole genome mutation analysis to screen for functional noncoding mutations that influence protein factor binding. Recurrent mutations were identified in the promoter of CDC20 gene. These CDC20 promoter hotspot mutations disrupt the binding of ELK4 transcription repressor, lead to the up-regulation of CDC20 transcription. Physiologically ELK4 binds to the unmutated hotspot sites and is involved in DNA damage-induced CDC20 transcriptional repression. Overall, our study not only identifies a detailed mechanism for CDC20 gene deregulation in human cancers but also finds functional noncoding genetic alterations, with implications for the further development of function-based noncoding driver discovery pipelines.
