Identification of a p53-repressed gene module in breast cancer cells

// Takafumi Miyamoto 1 , Chizu Tanikawa 1 , Varalee Yodsurang 5 , Yao-Zhong Zhang 2 , Seiya Imoto 3 , Rui Yamaguchi 2 , Satoru Miyano 2 , Hidewaki Nakagawa 4 and Koichi Matsuda 5 1 Laboratory of Genome Technology, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan 2 Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan 3 Division of Health Medical Data Science, Health Intelligence Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan 4 Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan 5 Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan Correspondence to: Koichi Matsuda, email: // Keywords : p53, breast cancer, transcriptome analysis, adriamycin, gene module Received : January 27, 2017 Accepted : May 28, 2017 Published : July 26, 2017 Abstract The p53 protein is a sophisticated transcription factor that regulates dozens of target genes simultaneously in accordance with the cellular circumstances. Although considerable efforts have been made to elucidate the functions of p53-induced genes, a holistic understanding of the orchestrated signaling network repressed by p53 remains elusive. Here, we performed a systematic analysis to identify simultaneously regulated p53-repressed genes in breast cancer cells. Consequently, 28 genes were designated as the p53-repressed gene module, whose gene components were simultaneously suppressed in breast cancer cells treated with Adriamycin. A ChIP-seq database showed that p53 does not preferably bind to the region around the transcription start site of the p53-repressed gene module elements compared with that of p53-induced genes. Furthermore, we demonstrated that p21/CDKN1A plays a pivotal role in the suppression of the p53-repressed gene module in breast cancer cells. Finally, we showed that appropriate suppression of some genes belonging to the p53-repressed gene module contributed to a better prognosis of breast cancer patients. Taken together, these findings disentangle the gene regulatory network underlying the built-in p53-mediated tumor suppression system.