TGFβ1 Activates Lnc-APUE to Promote Tumor Metastasis via the Alu Element-Driven STAU1-Mediated Decay of CDH1 mRNA.

About 25% of long noncoding RNAs (lncRNAs) contain Alu elements, yet their functional significance remains largely unexplored. We previously found that lnc-APUE was upregulated in hepatocellular carcinoma (HCC) and correlated with high recurrence rates. However, the pathogenic roles of lnc-APUE upregulation in tumor metastasis and its underlying mechanism are still unknown. Here, we showed that an Alu element in lnc-APUE could base-pair with the Alu element in 3'-untranslated region of E-cadherin coding gene (CDH1), triggering CDH1 mRNA decay and E-cadherin loss, consequently enhancing hepatoma cell migration and invasion. These effects of lnc-APUE were abrogated by deleting or mutating its Alu element, or by silencing STAU1 or UPF1, two key components of the STAU1-mediated mRNA decay (SMD) pathway. Mouse xenograft models revealed that overexpression of wild-type lnc-APUE, but not Alu-deleted lnc-APUE, reduced E-cadherin levels and promoted tumor metastasis, whereas silencing lnc-APUE had opposite effects. Furthermore, TGFβ1 stimulation induced SMAD2 binding to the lnc-APUE promoter, activating its transcription. Silencing lnc-APUE blocked TGFβ1-driven migration and invasion, identifying lnc-APUE as a downstream target and critical mediator of TGFβ1 signaling. Collectively, we define a new TGFβ1/SMAD/lnc-APUE/E-cadherin axis: TGFβ1 activates lnc-APUE to promote cancer metastasis through Alu element-driven STAU1-mediated CDH1 mRNA decay and subsequent E-cadherin downregulation.