Modulation of alternative splicing induced by paclitaxel in human lung cancer

Ziran Zhu,Jinrui Zhang,Lili Zhi,Lijuan Zou,Haoyu Ji,Yang Wang,Han Liu,Jinyao Zhao,Wenjing Zhang,Dan Chen,Fang Huang

doi:10.1038/s41419-018-0539-4

Abstract

Paclitaxel is utilized as the first-line chemotherapeutic regimen for the majority of advanced non-small-cell lung carcinoma. However, whether paclitaxel could suppress cancer progression through modulating RNA alternative splicing remains largely unknown. Here, we demonstrated the effects of paclitaxel on cell proliferation inhibition, cell cycle arrest, and apoptosis. Mechanistically, paclitaxel leads to transcriptional alteration of networks involved in DNA replication and repair, chromosome segregation, chromatin silencing at rDNA, and mitosis at the transcriptional level. Moreover, paclitaxel regulates a number of cancer-associated RNA alternative splicing events, including genes involved in cellular response to DNA damage stimulus, preassembly of GPI anchor in ER membrane, transcription, and DNA repair. In particular, paclitaxel modulates the splicing of ECT2, a key factor involved in the regulation of cytokinesis. Briefly, paclitaxel favors the production of ECT2-S, the short splicing isoforms of ECT2, thereby inhibiting cancer cell proliferation. Our study provides mechanistic insights of paclitaxel on RNA alternative splicing regulation, thus to offer a potential novel route for paclitaxel to inhibit cancer progression.

Highlights

Lung cancer is one of the most common malignant cancers world-wide
Paclitaxel inhibits cell proliferation and induces cell cycle arrest and apoptosis We sought to investigate the effect of paclitaxel on lung cancer cells
We demonstrated that paclitaxel potently induced cell growth inhibition, G2/M cell cycle arrest, and apoptosis in lung cancer cells

Summary

Introduction

Lung cancer is one of the most common malignant cancers world-wide. In 2017, 222,500 new cancer cases and 155,870 deaths were estimated in lung and bronchus according to the American Cancer Society, in which, nonsmall-cell lung carcinoma (NSCLC) accounts for 83% of lung cancer[1]. Most patients with stage III and IV NSCLC receive chemotherapy with or without radiation. Paclitaxel, a microtubule inhibitor, is commonly used in advanced NSCLC treatment either in combination with platinum-based agents or as monotherapy[2]. It is well established that Paclitaxel functions by directly binding to polymerized β-tubulin, thereby resulting in perturbation. Almost 95% of genes are alternatively spliced in humans. Alternative splicing (AS) of premessenger RNA (mRNA) leads to the production of multiple mature mRNAs and protein isoforms with distinct structural and functional properties[9]. Dysregulation of AS leads to aberrant protein isoforms, which may contribute to tumor initiation, progression, and therapeutic treatments difficulties[10, 11]. In NSCLC, some pre-mRNA splicing regulators have been demonstrated to be abnormally expressed, including SRSF1, SRSF2, SRPK1, and SRPK212.

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