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Genes Dev. 2014 Jun 1;28(11):1191-203. doi: 10.1101/gad.241968.114. Epub 2014 May 19.

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

Author information

1
Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA;
2
Department of Integrative Biology and Physiology, University of California at Los Angeles, Los Angeles, California 90095, USA;
3
Department of Structural Biology, St. Jude Proteomics Facility, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA; Department of Developmental Neurobiology, St. Jude Proteomics Facility, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA;
4
Department of Pharmacology, Emory University, Atlanta, Georgia 30322, USA;
5
Department of Radiation Oncology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA;
6
Department of Pathology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.

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 TGFβ signaling and identifies CD44 as a key downstream target of hnRNPM. hnRNPM ablation prevents TGFβ-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.

KEYWORDS:

CD44; EMT; ESRP1; TGFβ; alternative splicing; breast cancer metastasis; hnRNPM

PMID:
24840202
PMCID:
PMC4052765
DOI:
10.1101/gad.241968.114
[Indexed for MEDLINE]
Free PMC Article

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