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

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...

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Published inGenes & development Vol. 28; no. 11; pp. 1191 - 1203
Main Authors Xu, Yilin, Gao, Xin D, Lee, Jae-Hyung, Huang, Huilin, Tan, Haiyan, Ahn, Jaegyoon, Reinke, Lauren M, Peter, Marcus E, Feng, Yue, Gius, David, Siziopikou, Kalliopi P, Peng, Junmin, Xiao, Xinshu, Cheng, Chonghui
Format Journal Article
LanguageEnglish
Published United States Cold Spring Harbor Laboratory Press 01.06.2014
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Summary: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.
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Department of Maxillofacial Biomedical Engineering, School of Dentistry, Kyung Hee University, Seoul 130-701, Korea.
Present address: 8Department of Life and Nanopharmaceutical Sciences
ISSN:0890-9369
1549-5477
DOI:10.1101/gad.241968.114