4.7 Article

A Nucleolar Stress-Specific p53-miR-101 Molecular Circuit Functions as an Intrinsic Tumor-Suppressor Network

Journal

EBIOMEDICINE
Volume 33, Issue -, Pages 33-48

Publisher

ELSEVIER
DOI: 10.1016/j.ebiom.2018.06.031

Keywords

p53; Nucleolar stress; miR-101; Tumor-suppressor network

Funding

  1. Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO) [12-01]
  2. Japan Society for the Promotion of Science [15H04305]
  3. New Energy and Industrial Technology Development Organization of Japan Agency for Medical Research and Development (AMED) [JP17ae0101011h0004]
  4. AMED [JP17ck0106168h0003, JP18ck0106405h0001]
  5. Grants-in-Aid for Scientific Research [15H04305] Funding Source: KAKEN

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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 T'S network formed by nucleolar stress, and that mimicking activation of this circuit represents a promising strategy for cancer therapy. (C) 2018 The Authors. Published by Elsevier B.V.

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