CD44 splice isoform switching determines breast cancer stem cell state
- Honghong Zhang1,2,5,
- Rhonda L. Brown2,5,
- Yong Wei3,
- Pu Zhao1,
- Sali Liu1,2,
- Xuan Liu1,
- Yu Deng1,
- Xiaohui Hu1,
- Jing Zhang1,
- Xin D. Gao2,
- Yibin Kang3,
- Arthur M. Mercurio4,
- Hira Lal Goel4 and
- Chonghui Cheng1,2
- 1Lester and Sue Smith Breast Center, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA;
- 2Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA;
- 3Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA;
- 4Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA
- Corresponding author: chonghui.cheng{at}bcm.edu
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↵5 These authors contributed equally to this work.
Abstract
Although changes in alternative splicing have been observed in cancer, their functional contributions still remain largely unclear. Here we report that splice isoforms of the cancer stem cell (CSC) marker CD44 exhibit strikingly opposite functions in breast cancer. Bioinformatic annotation in patient breast cancer in The Cancer Genome Atlas (TCGA) database reveals that the CD44 standard splice isoform (CD44s) positively associates with the CSC gene signatures, whereas the CD44 variant splice isoforms (CD44v) exhibit an inverse association. We show that CD44s is the predominant isoform expressed in breast CSCs. Elimination of the CD44s isoform impairs CSC traits. Conversely, manipulating the splicing regulator ESRP1 to shift alternative splicing from CD44v to CD44s leads to an induction of CSC properties. We further demonstrate that CD44s activates the PDGFRβ/Stat3 cascade to promote CSC traits. These results reveal CD44 isoform specificity in CSC and non-CSC states and suggest that alternative splicing provides functional gene versatility that is essential for distinct cancer cell states and thus cancer phenotypes.
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Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.319889.118.
- Received August 14, 2018.
- Accepted December 11, 2018.
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