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

ABSTRACT 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.