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Cancer Res. 2018 Oct 9. pii: canres.1886.2018. doi: 10.1158/0008-5472.CAN-18-1886. [Epub ahead of print]

A p53-responsive microRNA network promotes cancer cell quiescence.

Author information

1
School of Biomedical Sciences and Pharmacy, University of Newcastle.
2
Translational Research Institute, Henan Provincial People's Hospital.
3
Oncology and Immunology Unit, Calvary Mater Newcastle Hospital.
4
Research and Innovation, University of Newcastle.
5
School of Medicine and Public Health, University of Newcastle.
6
Biomedical Sciences and Pharmacy, University of Newcastle.
7
Biomedical Sciences and Phamacy, University of Newcastle.
8
Histone Modification Group, Children's Cancer Institute Australia.
9
Cancer Research Unit, School of Biomedical Sciences, The University of Newcastle.
10
School of Medicine and Public Health, University of Newcastle Lei.Jin@newcastle.edu.au.
11
Faculty of Medicine and Public Health, The University of Newcastle.

Abstract

Cancer cells in quiescence (G0 phase) are resistant to death, and re-entry of quiescent cancer cells into the cell cycle plays an important role in cancer recurrence. Here we show that two p53-responsive microRNAs (miRNAs) utilize distinct but complementary mechanisms to promote cancer cell quiescence by facilitating stabilization of p27. Purified quiescent B16 mouse melanoma cells expressed higher levels of miRNA-27b-3p and miRNA-455-3p relative to their proliferating counterparts. Induction of quiescence resulted in increased levels of these miRNAs in diverse types of human cancer cell lines. Inhibition of miRNA-27b-3p or miRNA-455-3p reduced, whereas its overexpression increased, the proportion of quiescent cells in the population, indicating that these miRNAs promote cancer cell quiescence. Accordingly, cancer xenografts bearing miRNA-27b-3p or miRNA-455-3p mimics were retarded in growth. miRNA-27b-3p targeted cyclin-dependent kinase regulatory subunit 1 (CKS1B), leading to reduction in p27 polyubiquitination mediated by S-phase kinase-associated protein 2 (Skp2). miRNA-455-3p targeted CDK2-associated cullin domain 1 (CACUL1), which enhanced CDK2-mediated phosphorylation of p27 necessary for its polyubiquitination. Of note, the gene encoding miRNA-27b-3p was embedded in the intron of the chromosome 9 open reading frame 3 gene that was transcriptionally activated by p53. Similarly, the host gene of miRNA-455-3p, collagen alpha-1 chain, was also a p53 transcriptional target. Collectively, our results identify miRNA-27b-3p and miRNA-455-3p as important regulators of cancer cell quiescence in response to p53 and suggest that manipulating miRNA-27b-3p and miRNA-455-3p may constitute novel therapeutic avenues for improving outcomes of cancer treatment.

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