An alternative splicing switch in FLNB promotes the mesenchymal cell state in human breast cancer

Ji Li, Peter S. Choi, Christine L. Chaffer, Katherine Labella, Justin H. Hwang, Andrew O. Giacomelli, Jong Wook Kim, Nina Ilic, John G. Doench, Seav Huong Ly, Chao Dai, Kimberly Hagel, Andrew L. Hong, Ole Gjoerup, Shom Goel, Jennifer Y. Ge, David E. Root, Jean J. Zhao, Angela N. Brooks, Robert A. WeinbergWilliam C. Hahn

Research output: Contribution to journalArticlepeer-review

Abstract

Alternative splicing of mRNA precursors represents a key gene expression regulatory step and permits the generation of distinct protein products with diverse functions. In a genome-scale expression screen for inducers of the epithelial-to-mesenchymal transition (EMT), we found a striking enrichment of RNA-binding proteins. We validated that QKI and RBFOX1 were necessary and sufficient to induce an intermediate mesenchymal cell state and increased tumorigenicity. Using RNA-seq and eCLIP analysis, we found that QKI and RBFOX1 coordinately regulated the splicing and function of the actin-binding protein FLNB, which plays a causal role in the regulation of EMT. Specifically, the skipping of FLNB exon 30 induced EMT by releasing the FOXC1 transcription factor. Moreover, skipping of FLNB exon 30 is strongly associated with EMT gene signatures in basal-like breast cancer patient samples. These observations identify a specific dysregulation of splicing, which regulates tumor cell plasticity and is frequently observed in human cancer.

Original languageEnglish (US)
Article numbere37184
JournaleLife
Volume7
DOIs
StatePublished - Jul 30 2018
Externally publishedYes

Bibliographical note

Funding Information:
We thank Andy Aguirre, Joyce O’Connell, Nicole Burr, Hans Widlund, Bärbel Schröfelbauerand other members of the Hahn lab and Weinberg lab for helpful discussion. We thank Dr. Arnoud Sonnenberg (Netherlands Cancer Institute) for providing expression plasmids for two isoforms of FLNB. This work was supported in part by US NIH grants R01 CA130988, U01 CA176058, a Susan G. Komen Breast Cancer Postdoctoral Fellowship - Basic and Translational (PDF14300517) (J.L.), a Terri Brodeur Breast Cancer Foundation Grant (J.L.) and an NIH Pathway to Independence Award (K99 CA208028) (P.S.C.). W.C.H. is a consultant for Novartis.

Publisher Copyright:
© 2018, eLife Sciences Publications Ltd. All rights reserved.

Keywords

  • Alternative splicing
  • Basal-like breast cancer
  • EMT
  • FLNB
  • QKI
  • RBFOX1

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