Musashi proteins are post-transcriptional regulators of the epithelial-luminal cell state

Abstract

The conserved Musashi (Msi) family of RNA binding proteins are expressed in stem/progenitor and cancer cells, but generally absent from differentiated cells, consistent with a role in cell state regulation. We found that Msi genes are rarely mutated but frequently overexpressed in human cancers and are associated with an epithelial-luminal cell state. Using ribosome profiling and RNA-seq analysis, we found that Msi proteins regulate translation of genes implicated in epithelial cell biology and epithelial-to-mesenchymal transition (EMT), and promote an epithelial splicing pattern. Overexpression of Msi proteins inhibited the translation of Jagged1, a factor required for EMT, and repressed EMT in cell culture and in mammary gland in vivo. Knockdown of Msis in epithelial cancer cells promoted loss of epithelial identity. Our results show that mammalian Msi proteins contribute to an epithelial gene expression program in neural and mammary cell types.

DOI: http://dx.doi.org/10.7554/eLife.03915.001

eLife digest

All living things start life as a single cell, but many organisms develop into a collection of different, specialized cells. Most of the cells in an organism can only divide to make more of the same type of cell; however, stem cells are different because they can ‘differentiate’ and develop into several different cell types.

A key step in the development of an embryo is called the epithelial-to-mesenchymal transition, in which an epithelial cell—a cell type that normally lines body surfaces and cavities—begins to crawl away from the tissue it is in and starts to differentiate. This transition also allows cancer cells to leave tumors and spread around the body, in a process known as metastasis.

In mammals, two proteins called Musashi1 and Musashi2 are abundant in stem cells and brain cancers, but are rarely found in specialized tissues and cells. Katz, Li et al. now find that the Musashi proteins are also often overexpressed in human breast, lung, and prostate tumors. In addition, Musashi proteins are much less abundant in cells that have completed an epithelial-to-mesenchymal transition.

When Katz, Li et al. artificially reduced the amounts of Musashi proteins in breast cancer cells, the cells migrated and dispersed, as if becoming mesenchymal cells. Furthermore, many of the genes normally used in epithelial cells were switched off. In comparison, artificially increasing the levels of Musashi proteins halted the movement of mesenchymal cells and led to increased levels of genes used in epithelial cells, as if they were reverting to epithelial cells. Therefore, it appears that the Musashi proteins prevent epithelial cells from developing mesenchymal properties.

Katz, Li et al. investigated how Musashi proteins work at the molecular level by studying neural and mammary cells in mice. This revealed that Musashi proteins control the steps that lead to the epithelial-to-mesenchymal transition by binding to the tail end of the RNA molecules that include the instructions to make certain proteins. This affects how often these proteins can be made from the RNA molecules. Katz, Li et al. suggest that Musashi proteins may similarly control the behavior of progenitor and stem cells in many other tissues as well; however, further study is needed to confirm this.

DOI: http://dx.doi.org/10.7554/eLife.03915.002