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) 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.
Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA;
Yilin
Y
Xu
Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA;
Xin D
XD
Gao
Department of Integrative Biology and Physiology, University of California at Los Angeles, Los Angeles, California 90095, USA;
Jae-Hyung
JH
Lee
Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA;
Huilin
H
Huang
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;
Haiyan
H
Tan
Department of Integrative Biology and Physiology, University of California at Los Angeles, Los Angeles, California 90095, USA;
Jaegyoon
J
Ahn
Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA;
Lauren M
LM
Reinke
Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA;
Marcus E
ME
Peter
Department of Pharmacology, Emory University, Atlanta, Georgia 30322, USA;
Yue
Y
Feng
Department of Radiation Oncology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA;
David
D
Gius
Department of Pathology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
Kalliopi P
KP
Siziopikou
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;
Junmin
J
Peng
Department of Integrative Biology and Physiology, University of California at Los Angeles, Los Angeles, California 90095, USA;
Xinshu
X
Xiao
Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA;
Chonghui
C
Cheng
D017398:Alternative Splicing; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000503:physiopathology* / Q000556:secondary; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D034761:Heterogeneous-Nuclear Ribonucleoprotein Group M / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009362:Neoplasm Metastasis / Q000235:genetics / Q000503:physiopathology*; D020033:Protein Isoforms / Q000378:metabolism; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
D034761:Heterogeneous-Nuclear Ribonucleoprotein Group M; D018960:Hyaluronan Receptors; D020033:Protein Isoforms; D053773:Transforming Growth Factor beta1
CD44; EMT; ESRP1; TGFβ; alternative splicing; breast cancer metastasis; hnRNPM