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

• Type of Material: Article
• Authors: Yilin Xu, Northwestern University; Xin D. Gao, Northwestern University; Jae-Hyung Lee, University of California Los Angeles; Huilin Huang, Northwestern University; Haiyan Tan, St. Jude Children’s Research Hospital; Jaegyoon Ahn, University of California Los Angeles; Lauren M. Reinke, Northwestern University; Marcus E. Peter, Northwestern University; Yue Feng, Emory University; David Gius, Northwestern University; Kalliopi P. Siziopikou, Northwestern University; Junmin Peng, St. Jude Children’s Research Hospital; Xinshu Xiao, University of California Los Angeles; Chonghui Cheng, Northwestern University
• Language: English
• Date: 2014-06-01
• Publisher: Cold Spring Harbor Laboratory Press
• Publication Version: Final Published Version
• Copyright Statement: © 2014 Xu et al.; Published by Cold Spring Harbor Laboratory Press
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1101/gad.241968.114
• Title of Journal or Parent Work: Genes and Development
• ISSN: 0890-9369
• Volume: 28
• Issue: 11
• Start Page: 1191
• End Page: 1203
• Grant/Funding Information: This research was supported in part by grants from the American Cancer Society (RSG-09-181 to J.P.), the US National Institutes of Health (R01HG006264 and U01HG007013 to X.X.), and the American Cancer Society (RSG-09-252), the US National Institutes of Health (R01GM110146 and R01CA182467), the H Foundation, the A Sister’s Hope Foundation, and the Lynn Sage Breast Cancer Research Foundation and Scholar Award (to C.C.).
• Keywords: CHRONIC LYMPHOCYTIC-LEUKEMIA; TUMOR; CD44; hnRNPM; Cell Biology; TRANSCRIPTOME; STEM-CELLS; CELL BIOLOGY; Life Sciences & Biomedicine; GENETICS & HEREDITY; TRACT-BINDING-PROTEIN; ESRP1; Genetics & Heredity; TGF beta; Science & Technology; FACTOR SRSF1; DEVELOPMENTAL BIOLOGY; CARCINOMA; IDENTIFICATION; breast cancer metastasis; EMT; alternative splicing; EPITHELIAL-MESENCHYMAL TRANSITION; Developmental Biology
• Research Categories: Health Sciences, Pharmacology; Health Sciences, Oncology; Biology, Genetics

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.