Dataset Information

MicroRNA let-7b regulates genomic balance by targeting Aurora B kinase.

ABSTRACT: The let-7 microRNA (miRNA) family has been implicated in the regulation of diverse cellular processes and disease pathogenesis. In cancer, loss-of-function of let-7 miRNAs has been linked to tumorigenesis via increased expression of target oncogenes. Excessive proliferation rate of tumor cells is often associated with deregulation of mitotic proteins. Here, we show that let-7b contributes to the maintenance of genomic balance via targeting Aurora B kinase, a key regulator of the spindle assembly checkpoint (SAC). Our results indicate that let-7b binds to Aurora B kinase 3'UTR reducing mRNA and protein expression of the kinase. In cells, excess let-7b induced mitotic defects characteristic to Aurora B perturbation including increased rate of polyploidy and multipolarity, and premature SAC inactivation that leads to forced exit from chemically induced mitotic arrest. Moreover, the frequency of aneuploid HCT-116 cells was significantly increased upon let-7b overexpression compared to controls. Interestingly, together with a chemical Aurora B inhibitor, let-7b had an additive effect on polyploidy induction in HeLa cells. In breast cancer patients, reduced let-7b expression was found to be associated with increased Aurora B expression in grade 3 tumors. Furthermore, let-7b was found downregulated in the most aggressive forms of breast cancer determined by clinicopathological parameters. Together, our findings suggest that let-7b contributes to the fidelity of cell division via regulation of Aurora B. Moreover, the loss of let-7b in aggressive tumors may drive tumorigenesis by up-regulation of Aurora B and other targets of the miRNA, which further supports the role of let-7b in tumor suppression.

SUBMITTER: Maki-Jouppila JH

PROVIDER: S-EPMC5528760 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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MicroRNA let-7b regulates genomic balance by targeting Aurora B kinase.

Mäki-Jouppila Jenni Heidi Eveliina JH Pruikkonen Sofia S Tambe Mahesh Balasaheb MB Aure Miriam Ragle MR Halonen Tuuli T Salmela Anna-Leena AL Laine Leena L Børresen-Dale Anne-Lise AL Kallio Marko Johannes MJ

Molecular oncology 20150127 6

The let-7 microRNA (miRNA) family has been implicated in the regulation of diverse cellular processes and disease pathogenesis. In cancer, loss-of-function of let-7 miRNAs has been linked to tumorigenesis via increased expression of target oncogenes. Excessive proliferation rate of tumor cells is often associated with deregulation of mitotic proteins. Here, we show that let-7b contributes to the maintenance of genomic balance via targeting Aurora B kinase, a key regulator of the spindle assembly ...[more]

PMID: 25682900

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Project description:Aurora kinase A (AURKA) has been implicated in the regulation of cell cycle progression, mitosis and a key number of oncogenic signaling pathways in various malignancies. However, little is known about its role in gastric cancer prognosis and genotoxic resistance. Here we found that AURKA was highly overexpressed in gastric cancer and inversely correlated with disease prognosis. Overexpression of AURKA exacerbated gastric cancer drug resistance through upregulating the expression of the anti-apoptotic protein Survivin. Conversely, we demonstrated that AURKA depletion caused a decrease in Survivin protein levels by increasing its ubiquitylation and degradation. Mass spectrometric analysis revealed that upon AURKA depletion, Survivin bound to the FBXL7 E3 ubiquitin ligase, which induced ubiquitin-proteasome degradation of Survivin. In addition, we showed that AURKA regulated FBXL7 both at the levels of transcription and translation. Moreover, proteomic analysis of nuclear AURKA-interacting proteins identified Forkhead box protein P1 (FOXP1). We next showed that AURKA was required for FBXL7 transcription and that AURKA negatively regulated FOXP1-mediated FBXL7 expression. The physiological relevance of the regulation of Survivin by AURKA through the FOXP1-FBXL7 axis was further underscored by the significant positive correlations between AURKA and Survivin expression in gastric cancer patient samples. Moreover, the AURKA depletion or kinase inhibition-induced apoptotic cell death could be reversed by Survivin ectopic overexpression, further supporting that AURKA regulated Survivin to enhance drug resistance. In agreement, inhibition of AURKA synergistically enhanced the cytotoxic effect of DNA-damaging agents in cancer cells by suppressing Survivin expression. Taken together, our data suggest that AURKA restricts Survivin ubiquitylation and degradation in gastric cancer to promote drug resistance and hence the AURKA-Survivin axis can be targeted to promote the efficacy of DNA-damaging agents in gastric cancer.

Dataset Information

MicroRNA let-7b regulates genomic balance by targeting Aurora B kinase.

Publications

MicroRNA let-7b regulates genomic balance by targeting Aurora B kinase.

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