- Title
- A p53-responsive miRNA network promotes cancer cell quiescence
- Creator
- La, Ting; Liu, Guang Zhi; Guo, Su Tang; Liu, Tao; Thorne, Rick F.; Jin, Lei; Zhang, Xu Dong; Farrelly, Margaret; Cole, Nicole; Feng, Yu Chen; Zhang, Yuan Yuan; Sherwin, Simonne K.; Yari, Hamed; Tabatabaee, Hessam; Yan, Xu Guang
- Relation
- Cancer Research Vol. 78, Issue 23, p. 6666-6679
- Publisher Link
- http://dx.doi.org/10.1158/0008-5472.CAN-18-1886
- Publisher
- American Association for Cancer Research
- Resource Type
- journal article
- Date
- 2018
- Description
- 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 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 (CAC1), 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 (XXVII) 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. Significance: Two novel p53-responsive microRNAs whose distinct mechanisms of action both stabilize p27 to promote cell quiescence and may serve as therapeutic avenues for improving outcomes of cancer treatment.
- Subject
- cancer cells; quiescence; cancer; miRNA
- Identifier
- http://hdl.handle.net/1959.13/1407585
- Identifier
- uon:35745
- Identifier
- ISSN:0008-5472
- Rights
- © 2018 American Association for Cancer Research.
- Language
- eng
- Full Text
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