A microRNA miR-34a-regulated bimodal switch targets Notch in colon cancer stem cells
- PMID: 23642368
- PMCID: PMC3646336
- DOI: 10.1016/j.stem.2013.03.002
A microRNA miR-34a-regulated bimodal switch targets Notch in colon cancer stem cells
Abstract
microRNAs regulate developmental cell-fate decisions, tissue homeostasis, and oncogenesis in distinct ways relative to proteins. Here, we show that the tumor suppressor microRNA miR-34a is a cell-fate determinant in early-stage dividing colon cancer stem cells (CCSCs). In pair-cell assays, miR-34a distributes at high levels in differentiating progeny, whereas low levels of miR-34a demarcate self-renewing CCSCs. Moreover, miR-34a loss of function and gain of function alter the balance between self-renewal versus differentiation both in vitro and in vivo. Mechanistically, miR-34a sequesters Notch1 mRNA to generate a sharp threshold response where a bimodal Notch signal specifies the choice between self-renewal and differentiation. In contrast, the canonical cell-fate determinant Numb regulates Notch levels in a continuously graded manner. Altogether, our findings highlight a unique microRNA-regulated mechanism that converts noisy input into a toggle switch for robust cell-fate decisions in CCSCs.
Copyright © 2013 Elsevier Inc. All rights reserved.
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Comment in
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miR-34a sets the "sweet spot" for notch in colorectal cancer stem cells.Cell Stem Cell. 2013 May 2;12(5):499-501. doi: 10.1016/j.stem.2013.04.018. Cell Stem Cell. 2013. PMID: 23642356
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