SRSF1 inhibits autophagy through regulating Bcl-x splicing and interacting with PIK3C3 in lung cancer  

作　　者：Yuesheng Lv Wenjing Zhang Jinyao Zhao Bing Sun Yangfan Qi Haoyu Ji Chaoqun Chen Jinrui Zhang Junxiu Sheng Taishu Wang Daniel Dominguez Han Liu Quentin Liu Songshu Meng Xiaoling Li Yang Wang 

机构地区：[1]Second Affiliated Hospital,Institute of Cancer Stem Cell,Dalian Medical University,Dalian,China [2]Department of Thoracic Surgery,First Affiliated Hospital,Dalian Medical University,Dalian,China [3]Department of Radiation Oncology,First Affiliated Hospital,Dalian Medical University,Dalian,China [4]Department of Pharmacology,University of North Carolina at Chapel Hill,Chapel Hill,NC,USA [5]Signal Transduction Laboratory,National Institute of Environmental Health Sciences,Research Triangle Park,NC,USA

出　　处：《Signal Transduction and Targeted Therapy》2021年第4期1265-1279,共15页信号转导与靶向治疗（英文）

基　　金：This work was supported by the National Natural Science Foundation of China(81830088,81422038,91540110,and 31471235 to Y.W.,81872247 and 31400726 to W.Z.);the Department of Education of Liaoning Province(the"Liaoning Supports High Level Talents Innovation and Entrepreneurship Program"XLYC1802067 to Y.W.);the Department of Science and Technology of Dalian City(the HDalian Supports High Level Talents Innovation and Entrepreneurship Program" 2016RJ02 to Y.W.);the Newton Advanced Fellowship from the Academy of Medical Sciences in UK(JXR11831 to Y.W.).

摘　　要：Alternative splicing is a critical process to generate protein diversity.However,whether and how alternative splicing regulates autophagy remains largely elusive.Here we systematically identify the splicing factor SRSF1 as an autophagy suppressor.Specifically,SRSF1 inhibits autophagosome formation by reducing the accumulation of LC3-ⅡI and numbers of autophagosomes in different cell lines.Mechanistically,SRSF1 promotes the splicing of the long isoform of Bcl-x that interacts with Beclinl,thereby dissociating the Beclin1-PIK3C3 complex.In addition,SRSF1 also directly interacts with PIK3C3 to disrupt the interaction between Beclinl and PIK3C3.Consequently,the decrease of SRSF1 stabilizes the Beclinl and PIK3C3 complex and activates autophagy.Interestingly,SRSF1 can be degraded by starvation-and oxidative stresses-induced autophagy through interacting with LC3-Ⅱ,whereas reduced SRSF1 further promotes autophagy.This positive feedback is critical to inhibiting Gefitinib-resistant cancer cell progression both in vitro and in vivo.Consistently,the expression level of SRSF1 is inversely correlated to LC3 level in clinical cancer samples.Our study not only provides mechanistic insights of alternative splicing in autophagy regulation but also discovers a new regulatory role of SRSF1 in tumorigenesis,thereby offering a novel avenue for potential cancer therapeutics.

关 键 词：BECLIN1 BECLIN thereby 

分 类 号：R730[医药卫生—肿瘤]