Cell type-restricted activity of hnRNPM promotes breast cancer metastasis via regulating alternative splicing

Yilin Xu, Xin D. Gao, Jae Hyung Lee, Huilin Huang, Haiyan Tan, Jaegyoon Ahn, Lauren M. Reinke, Marcus E. Peter, Yue Feng, David Gius, Kalliopi P. Siziopikou, Junmin Peng, Xinshu Xiao, Chonghui Cheng*

*Corresponding author for this work

Research output: Contribution to journalArticle

100 Scopus citations

Abstract

Tumor metastasis remains the major cause of cancer-related death, but its molecular basis is still not well understood. Here we uncovered a splicing-mediated pathway that is essential for breast cancer metastasis. We show that the RNA-binding protein heterogeneous nuclear ribonucleoprotein M (hnRNPM) promotes breast cancer metastasis by activating the switch of alternative splicing that occurs during epithelial-mesenchymal transition (EMT). Genome-wide deep sequencing analysis suggests that hnRNPM potentiates TGFb signaling and identifies CD44 as a key downstream target of hnRNPM. hnRNPM ablation prevents TGFb-induced EMT and inhibits breast cancer metastasis in mice, whereas enforced expression of the specific CD44 standard (CD44s) splice isoform overrides the loss of hnRNPM and permits EMT and metastasis. Mechanistically, we demonstrate that the ubiquitously expressed hnRNPM acts in a mesenchymal-specific manner to precisely control CD44 splice isoform switching during EMT. This restricted cell-type activity of hnRNPM is achieved by competition with ESRP1, an epithelial splicing regulator that binds to the same cis-regulatory RNA elements as hnRNPM and is repressed during EMT. Importantly, hnRNPM is associated with aggressive breast cancer and correlates with increased CD44s in patient specimens. These findings demonstrate a novel molecular mechanism through which tumor metastasis is endowed by the hnRNPM-mediated splicing program.

Original languageEnglish (US)
Pages (from-to)1191-1203
Number of pages13
JournalGenes and Development
Volume28
Issue number11
DOIs
StatePublished - Jun 1 2014

Keywords

  • Alternative splicing
  • Breast cancer metastasis
  • CD44
  • EMT
  • ESRP1
  • TGFβ
  • hnRNPM

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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  • Cite this

    Xu, Y., Gao, X. D., Lee, J. H., Huang, H., Tan, H., Ahn, J., Reinke, L. M., Peter, M. E., Feng, Y., Gius, D., Siziopikou, K. P., Peng, J., Xiao, X., & Cheng, C. (2014). Cell type-restricted activity of hnRNPM promotes breast cancer metastasis via regulating alternative splicing. Genes and Development, 28(11), 1191-1203. https://doi.org/10.1101/gad.241968.114