A microRNA miR-34a-Regulated Bimodal Switch Targets Notch in Colon Cancer Stem Cells

• Published in: Cell stem cell 2013-05, Vol.12 (5), p.602-615
• Main Authors: Bu, Pengcheng, Chen, Kai-Yuan, Chen, Joyce Huan, Wang, Lihua, Walters, Jewell, Shin, Yong Jun, Goerger, Julian P., Sun, Jian, Witherspoon, Mavee, Rakhilin, Nikolai, Li, Jiahe, Yang, Herman, Milsom, Jeff, Lee, Sang, Zipfel, Warren, Jin, Moonsoo M., Gümüş, Zeynep H., Lipkin, Steven M., Shen, Xiling
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Asymmetric Cell Division; Carcinogenesis - genetics; Cell Differentiation - genetics; Cell Line, Tumor; Cell Lineage - genetics; Cell Proliferation; Colonic Neoplasms - genetics; Colonic Neoplasms - pathology; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Membrane Proteins - metabolism; MicroRNAs - genetics; MicroRNAs - metabolism; Middle Aged; Neoplasm Staging; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Nerve Tissue Proteins - metabolism; Protein Transport; Receptors, Notch - metabolism; Signal Transduction - genetics; Xenograft Model Antitumor Assays
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2013.03.002

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. [Display omitted] ► miR-34a regulates colon cancer stem cell asymmetric division ► miR-34a generates a sharp threshold response ► miR-34a converts Notch signaling into a toggle switch ► Binary Notch levels specify self-renewal versus differentiation The tumor suppressor microRNA miR-34a generates cell-fate asymmetry in colon cancer stem cells by sequestering Notch1 mRNA.