A Nucleolar Stress–Specific p53–miR-101 Molecular Circuit Functions as an Intrinsic Tumor-Suppressor NetworkResearch in context
Yuko Fujiwara,
Motonobu Saito,
Ana I. Robles,
Momoyo Nishida,
Fumitaka Takeshita,
Masatoshi Watanabe,
Takahiro Ochiya,
Jun Yokota,
Takashi Kohno,
Curtis C. Harris,
Naoto Tsuchiya
Affiliations
Yuko Fujiwara
Laboratory of Molecular Carcinogenesis, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
Motonobu Saito
Division of Genome Biology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
Ana I. Robles
Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4258, USA
Momoyo Nishida
Laboratory of Molecular Carcinogenesis, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Laboratory for Medical Engineering, Division of Materials and Chemical Engineering, Graduate School of Engineering, Yokohama National University, 79-1 Tokiwadai, Hodogaya-ku, Yokohama 240-8501, Japan
Fumitaka Takeshita
Division of Cellular and Molecular Medicine, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
Masatoshi Watanabe
Laboratory for Medical Engineering, Division of Materials and Chemical Engineering, Graduate School of Engineering, Yokohama National University, 79-1 Tokiwadai, Hodogaya-ku, Yokohama 240-8501, Japan
Takahiro Ochiya
Division of Cellular and Molecular Medicine, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
Jun Yokota
Division of Genome Biology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Barcelona, Spain
Takashi Kohno
Division of Genome Biology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
Curtis C. Harris
Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4258, USA
Naoto Tsuchiya
Laboratory of Molecular Carcinogenesis, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Corresponding author at: 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
Background: Activation of intrinsic p53 tumor-suppressor (TS) pathways is an important principle underlying cancer chemotherapy. It is necessary to elucidate the precise regulatory mechanisms of these networks to create new treatment strategies. Methods: Comprehensive analyses were carried out by microarray. Expression of miR-101 was analyzed by clinical samples of lung adenocarcinomas. Findings: We discovered a functional link between p53 and miR-101, which form a molecular circuit in response to nucleolar stress. Inhibition of RNA polymerase I (Pol I) transcription resulted in the post-transcriptional activation of miR-101 in a p53-dependent manner. miR-101 induced G2 phase–specific feedback regulation of p53 through direct repression of its target, EG5, resulting in elevated phosphorylation of ATM. In lung cancer patients, low expression of miR-101 was associated with significantly poorer prognosis exclusively in p53 WT cases. miR-101 sensitized cancer cells to Pol I transcription inhibitors and strongly repressed xenograft growth in mice. Interestingly, the most downstream targets of this circuit included the inhibitor of apoptosis proteins (IAPs). Repression of cIAP1 by a selective inhibitor, birinapant, promoted activation of the apoptosis induced by Pol I transcription inhibitor in p53 WT cancer cells. Interpretation: Our findings indicate that the p53–miR-101 circuit is a component of an intrinsic TS network formed by nucleolar stress, and that mimicking activation of this circuit represents a promising strategy for cancer therapy. Fund: National Institute of Biomedical Innovation, Ministry of Education, Culture, Sports & Technology of Japan, Japan Agency for Medical Research and Development. Keywords: p53, Nucleolar stress, miR-101, Tumor-suppressor network
