ESRP1 regulates alternative splicing of CARM1 to sensitize small cell lung cancer cells to chemotherapy by inhibiting TGF-β/Smad signaling
Meng Zheng, Yuchun Niu, Junguo Bu, Shumei Liang, Zhilin Zhang, Jianhua Liu, Linlang Guo, Zhihua Zhang, Qiongyao Wang
Abstract
. Through mRNA transcriptome sequencing, we found that ESRP1 regulates coactivator-associated arginine methyltransferase 1 (CARM1) to produce two different transcripts CARM1FL and CARM1ΔE15 by alternative splicing. ESRP1 affects the chemoresistance of SCLC by changing the content of different transcripts of CARM1. Furthermore, CARM1 regulates arginine methylation of Smad7, activates the TGF-β/Smad pathway and induces epithelial-to-mesenchymal transition (EMT), thereby promoting SCLC chemoresistance. Collectively, our study firstly demonstrates that ESRP1 inhibits the TGF-β/Smad signaling pathway by regulating alternative splicing of CARM1, thereby reversing chemoresistance of SCLC. The splicing factor ESRP1 may serve as a new drug resistance marker molecule and a potential therapeutic target in SCLC patients.