A Wnt-induced lncRNA-DGCR5 splicing switch drives tumor-promoting inflammation in esophageal squamous cell carcinoma

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. [Display omitted] •Wnt/β-catenin signaling induces alternative splicing of lncRNA-DGCR5 in ESCC•Active β-catenin promotes FUS-mediated assembly of the spliceosome on DGCR5 RNA•The short DGCR5 drives tumor-promoting inflammation via inhibition of TTP•Splice-switching oligonucleotides targeting DGCR5 suppress ESCC tumor growth Li et al. find that, in Wnt-activated ESCC cells, nuclear β-catenin induces a splicing switch of lncRNA-DGCR5 to inhibit TTP activity, leading to cytokine mRNA stabilization, production, and tumor-promoting inflammation, suggesting that targeting DGCR5 splicing switch is a promising therapeutic strategy against ESCC.