A microRNA miR-34a-regulated bimodal switch targets Notch in colon cancer stem cells.

TitleA microRNA miR-34a-regulated bimodal switch targets Notch in colon cancer stem cells.
Publication TypeJournal Article
Year of Publication2013
AuthorsP Bu, K-Y Chen, JH Chen, L Wang, J Walters, YJ Shin, JP Goerger, J Sun, M Witherspoon, N Rakhilin, J Li, H Yang, J Milsom, S Lee, W Zipfel, MM Jin, ZH Gümüş, SM Lipkin, and X Shen
JournalCell Stem Cell
Volume12
Issue5
Start Page602
Pagination602 - 615
Date Published05/2013
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.

DOI10.1016/j.stem.2013.03.002
Short TitleCell Stem Cell