CstF64-Induced Shortening of the <i>BID</i> 3'UTR Promotes Esophageal Squamous Cell Carcinoma Progression by Disrupting ceRNA Cross-talk with <i>ZFP36L2</i>.

Abstract

The majority of human genes have multiple polyadenylation sites, which are differentially used through the process of alternative polyadenylation (APA). Dysregulation of APA contributes to numerous diseases, including cancer. However, specific genes subject to APA that impact oncogenesis have not been well characterized, and many cancer APA landscapes remain underexplored. Here, we used dynamic analyses of APA from RNA-seq (DaPars) to define both the 3'UTR APA profile in esophageal squamous cell carcinoma (ESCC) and to identify 3'UTR shortening events that may drive tumor progression. In four distinct squamous cell carcinoma datasets, <i>BID</i> 3'UTRs were recurrently shortened and <i>BID</i> mRNA levels were significantly upregulated. Moreover, system correlation analysis revealed that CstF64 is a candidate upstream regulator of <i>BID</i> 3'UTR length. Mechanistically, a shortened <i>BID</i> 3'UTR promoted proliferation of ESCC cells by disrupting competing endogenous RNA (ceRNA) cross-talk, resulting in downregulation of the tumor suppressor gene <i>ZFP36L2</i>. These <i>in vitro</i> and <i>in vivo</i> results were supported by human patient data whereby 3'UTR shortening of <i>BID</i> and low expression of <i>ZFP36L2</i> are prognostic factors of survival in ESCC. Collectively, these findings demonstrate that a key ceRNA network is disrupted through APA and promotes ESCC tumor progression.<b>Significance:</b> High-throughput analysis of alternative polyadenylation in esophageal squamous cell carcinoma identifies recurrent shortening of the <i>BID</i> 3'UTR as a driver of disease progression.