ESRP1 regulates alternative splicing of CARM1 to sensitize small cell lung cancer cells to chemotherapy by inhibiting TGF-β/Smad signaling.
ESRP1 regulates alternative splicing of CARM1 to sensitize small cell lung cancer cells to chemotherapy by inhibiting TGF-β/Smad signaling.
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ESRP1 调节 CARM1 的选择性剪接，通过抑制 TGF-β/Smad 信号传导使小细胞肺癌细胞对化疗敏感
DOI：
10.18632/aging.202295
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发表时间：
2021-01-20
期刊：
影响因子：
--
通讯作者：
Wang Q
中科院分区：
文献类型：
--
作者：
Zheng M;Niu Y;Bu J;Liang S;Zhang Z;Liu J;Guo L;Zhang Z;Wang Q
上皮剪接调节蛋白1（Epithelial splicing regulatory protein 1，ESRP 1）是一种调节mRNA选择性剪接的RNA结合蛋白。ESRP 1在多种癌症的化学抗性中起重要作用，包括乳腺癌、结肠癌和非小细胞肺癌。然而，ESRP 1在小细胞肺癌（SCLC）化疗耐药中的作用及其机制仍不清楚。在这项研究中，我们发现ESRP 1在SCLC化疗耐药细胞中的表达显著下调。ESRP 1在SCLC组织中的表达明显低于癌旁正常组织，且与总生存期呈正相关。ESRP 1的过表达增加了小细胞肺癌的化疗敏感性，并诱导细胞凋亡和细胞周期阻滞，而ESRP 1的敲低诱导相反的效果。ESRP 1在体内可抑制SCLC的生长。通过mRNA转录组测序，我们发现ESRP 1通过选择性剪接调节辅激活子相关精氨酸甲基转移酶1（carm 1）产生两种不同的转录本CARM 1 FL和CARM 1 ΔE15。ESRP 1通过改变CARM 1不同转录本的含量影响SCLC的化疗耐药性。此外，CARM 1调节Smad 7的精氨酸甲基化，激活TGF-β/Smad通路并诱导上皮向间充质转化（EMT），从而促进SCLC化学抗性。总之，我们的研究首次证明ESRP 1通过调节CARM 1的选择性剪接来抑制TGF-β/Smad信号通路，从而逆转SCLC的化疗耐药性。剪接因子ESRP 1可能成为小细胞肺癌新的耐药标志物和潜在的治疗靶点。
Epithelial splicing regulatory protein 1 (ESRP1) is an RNA-binding protein that regulates alternative splicing of mRNA. ESRP1 plays an important role in chemoresistance of various cancers, including breast cancer, colon cancer and non-small cell lung cancer. However, the role of ESRP1 and its mechanism in small cell lung cancer (SCLC) chemoresistance remains unclear. In this study, we found that ESRP1 is significantly downregulated in SCLC chemo-resistant cells compared with chemo-sensitive cells. Moreover, the expression of ESRP1 was significantly lower in SCLC tissues than that in normal adjacent tissues and positively correlated with overall survival. Overexpression of ESRP1 increased SCLC chemosensitivity, and induced cell apoptosis and cell cycle arrest, whereas knockdown of ESRP1 induced the opposite effects. ESRP1 could inhibit the growth of SCLC in vivo. 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.
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影响因子：
6.4
作者：
Eilertsen IA;Sveen A;Strømme JM;Skotheim RI;Nesbakken A;Lothe RA
通讯作者：
Lothe RA
影响因子：
--
作者：
Hayakawa, Akira;Saitoh, Masao;Miyazawa, Keiji
通讯作者：
Miyazawa, Keiji
TRA2A 通过调节选择性剪接促进三阴性乳腺癌的紫杉醇耐药性和肿瘤进展
影响因子：
5.7
作者：
Liu, Tieju;Sun, Huizhi;Sun, Baocun
通讯作者：
Sun, Baocun
DOI：
10.1261/rna.066712.118
发表时间：
2018-10
期刊：
RNA (New York, N.Y.)
影响因子：
--
作者：
Harvey SE;Xu Y;Lin X;Gao XD;Qiu Y;Ahn J;Xiao X;Cheng C
通讯作者：
Cheng C
影响因子：
8
作者：
Calabretta S;Bielli P;Passacantilli I;Pilozzi E;Fendrich V;Capurso G;Fave GD;Sette C
通讯作者：
Sette C