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TGF-β-induced alternative splicing of TAK1 promotes EMT and drug resistance

Oncogene volume 38, pages 3185–3200 (2019)Cite this article

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Abstract

Transforming growth factor-β (TGF-β) is major inducer of epithelial-to-mesenchymal transition (EMT), which associates with cancer cell metastasis and resistance to chemotherapy and targeted drugs, through both transcriptional and non-transcriptional mechanisms. We previously reported that, in cancer cells, heightened mitogenic signaling allows TGF-β-activated Smad3 to interact with poly(RC) binding protein 1 (PCBP1) and together they regulate many alternative splicing events that favors expression of protein isoforms essential for EMT, cytoskeletal rearrangement, and adherens junction signaling. Here we show that the exclusion of TGF-β-activated kinase 1 (TAK1) variable exon 12 requires another RNA-binding protein, Fox-1 homolog 2 (Rbfox2), which binds intronic sequences in front of exon 12 independently of the Smad3–PCBP1 complex. Functionally, exon 12-excluded TAK1∆E12 and full-length TAK1FL are distinct. The short isoform TAK1∆E12 is constitutively active and supports TGF-β-induced EMT and nuclear factor kappa B (NF-κB) signaling, whereas the full-length isoform TAK1FL promotes TGF-β-induced apoptosis. These observations offer a harmonious explanation for how a single TAK1 kinase can mediate the opposing responses of cell survival and apoptosis in response to TGF-β. They also reveal a propensity of the alternatively spliced TAK1 isoform TAK1∆E12 to cause drug resistance due to its activity in supporting EMT and NF-κB survival signaling.

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Acknowledgements

We thank Dr. K. Matsumoto for providing HA-TAK1 (∆E12) plasmids; Dr. ZG Liu for NFκB-Luc reporter construct; Dr. K Hunter, Dr. L. Yang, and Dr. T. Misteli for Met-1, 4T1, and hMSC cells, respectively. This research was supported by the intramural research program of the NIH, National Cancer Institute, Center for Cancer Research.

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  1. Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA

    Veenu Tripathi, Jee-Hye Shin, Christina H. Stuelten & Ying E. Zhang

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Tripathi, V., Shin, JH., Stuelten, C.H. et al. TGF-β-induced alternative splicing of TAK1 promotes EMT and drug resistance. Oncogene 38, 3185–3200 (2019). https://doi.org/10.1038/s41388-018-0655-8

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