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

Pengcheng Bu, Kai Yuan Chen, Joyce Huan Chen, Lihua Wang, Jewell Walters, Yong Jun Shin, Julian P. Goerger, Jian Sun, Mavee Witherspoon, Nikolai Rakhilin, Jiahe Li, Herman Yang, Jeff Milsom, Sang Lee, Warren Zipfel, Moonsoo M. Jin, Zeynep H. Gümüş, Steven M. Lipkin, Xiling Shen

Research output: Contribution to journalArticlepeer-review

321 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)602-615
Number of pages14
JournalCell Stem Cell
Volume12
Issue number5
DOIs
StatePublished - May 2 2013

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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