A Wnt-induced lncRNA-DGCR5 splicing switch drives tumor-promoting inflammation in esophageal squamous cell carcinoma
Yue Li,
Boyu Chen,
Xingyu Jiang,
Yudong Li,
Xin Wang,
Shumei Huang,
Xuxia Wu,
Yunyun Xiao,
Dongni Shi,
Xinjian Huang,
Lixin He,
Xiangfu Chen,
Ying Ouyang,
Jun Li,
Libing Song,
Chuyong Lin
Affiliations
Yue Li
Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
Boyu Chen
Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
Xingyu Jiang
Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
Yudong Li
Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
Xin Wang
Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
Shumei Huang
Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
Xuxia Wu
Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
Yunyun Xiao
Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
Dongni Shi
Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
Xinjian Huang
Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
Lixin He
Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
Xiangfu Chen
Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
Ying Ouyang
Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
Jun Li
Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; Corresponding author
Libing Song
Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Institute of Oncology, Tumor Hospital, Guangzhou Medical University, Guangzhou 511436, China; Corresponding author
Chuyong Lin
Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; Corresponding author
Summary: Alternative splicing (AS) is a critical mechanism for the aberrant biogenesis of long non-coding RNA (lncRNA). Although the role of Wnt signaling in AS has been implicated, it remains unclear how it mediates lncRNA splicing during cancer progression. Herein, we identify that Wnt3a induces a splicing switch of lncRNA-DGCR5 to generate a short variant (DGCR5-S) that correlates with poor prognosis in esophageal squamous cell carcinoma (ESCC). Upon Wnt3a stimulation, active nuclear β-catenin acts as a co-factor of FUS to facilitate the spliceosome assembly and the generation of DGCR5-S. DGCR5-S inhibits TTP’s anti-inflammatory activity by protecting it from PP2A-mediated dephosphorylation, thus fostering tumor-promoting inflammation. Importantly, synthetic splice-switching oligonucleotides (SSOs) disrupt the splicing switch of DGCR5 and potently suppress ESCC tumor growth. These findings uncover the mechanism for Wnt signaling in lncRNA splicing and suggest that the DGCR5 splicing switch may be a targetable vulnerability in ESCC.
