Journal
MOLECULAR CANCER RESEARCH
Volume 14, Issue 7, Pages 634-646Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1541-7786.MCR-16-0018
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Funding
- NIH NCI [NIH-CA 055536, NIH-CA 154663]
- Abney Foundation
- American Heart Association [10PRE3870024]
- National Institute of General Medicine [P30GM103331]
- MUSC Flow Cytometry Facility [P30GM103342]
- Cell & Molecular Imaging Shared Resource of MUSC [P30CA138313]
- Biorepository & Tissue Analysis Shared Resource, Hollings Cancer Center, MUSC
- Gene Targeting and Knockout Shared Resource at MUSC
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CDC27 is a core component of the anaphase-promoting complex/cyclosome (APC/C), a multisubunit E3 ubiquitin ligase, whose oscillatory activity is responsible for the metaphase-to-anaphase transition and mitotic exit. Here, in normal murine mammary gland epithelial cells (NMuMG), CDC27 expression is controlled posttranscriptionally through the RNA binding protein poly(rC) binding protein 1 (PCBP1)/heterogeneous nuclear ribonucleoprotein E1 (HNRNP E1). shRNA-mediated knockdown of HNRNP E1 abrogates translational silencing of the Cdc27 transcript, resulting in constitutive expression of CDC27. Dysregulated expression of CDC27 leads to premature activation of the G(2)-M-APC/C-CDC20 complex, resulting in the aberrant degradation of FZR1/CDH1, a cofactor of the G(1) and late G(2) -M-APC/C and a substrate normally reserved for the SCF-beta TRCP ligase. Loss of CDH1 expression and of APC/C-CDH1 activity, upon constitutive expression of CDC27, results in mitotic aberrations and aneuploidy in NMuMG cells. Furthermore, tissue microarray of breast cancer patient tumor samples reveals high CDC27 levels compared with nonneoplastic breast tissue and a significant correlation between disease recurrence and CDC27 expression. These results suggest that dysregulation of HNRNP E1-mediated translational regulation of Cdc27 leads to chromosomal instability and aneuploidy and that CDC27 expression represents a significant predictor of breast cancer recurrence. Implications: The RNA-binding protein HNRNP E1 mediates translational regulation of the cell-cycle regulator CDC27 and that dysregulation of CDC27 leads to aneuploidy. In addition, high CDC27 expression in breast cancer patient tumor specimens significantly predicts disease recurrence, suggesting a novel role for CDC27 as a predictor of relapse. (C)2016 AACR.
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