Abstract 3032: Direct regulation of alternative splicing by Smad3 through PCBP1 is essential to the tumor-promoting role of transforming growth factor beta1

Abstract

Abstract In advanced stages of cancers, TGF- β promotes tumor progression in conjunction with inputs from receptor tyrosine kinase pathways. However, the mechanisms that underpin the signaling cooperation and convert TGF- β from a potent growth inhibitor to a tumor promoter are not fully understood. In this work we report that TGF- β directly regulates alternative splicing of cancer stem cell marker CD44 through a phosphorylated T179 of SMAD3-mediated interaction with RNA-binding protein PCBP1. We show that TGF- β and EGF respectively induce SMAD3 and PCBP1 to colocalize in SC35 positive nuclear speckles, and the two proteins interact in the variable exon region of CD44 pre-mRNA to inhibit spliceosome assembly in favor of expressing the mesenchymal isoform CD44s over the epithelial isoform CD44E. We further show that the SMAD3-mediated alternative splicing is essential to the tumor-promoting role of TGF- β and has a global influence on protein products of genes instrumental to epithelial to mesenchymal transition and metastasis. Citation Format: Veenu Tripathi, Katherine M. Sixt, Xuan Xu, Ying E. Zhang. Direct regulation of alternative splicing by Smad3 through PCBP1 is essential to the tumor-promoting role of transforming growth factor beta1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3032. doi:10.1158/1538-7445.AM2017-3032