LAUSR

Significance Aberrant lncRNA expression is responsible for cancer progression and metastasis, positioning lncRNAs not only as biomarkers but also as promising therapeutic targets for curing cancer. A number of lncRNAs have been reported in ESCC but their mechanistic roles largely remain unknown. Wnt signaling pathways are often dysregulated in ESCC; however, the role of lncRNAs in such dysregulation was also undetermined. We found 6 lncRNAs that are significantly dysregulated and correlated with outcomes in ESCC patients. The most upregulated lncRNA, HERES, promotes cancer progression and epigenetically regulates canonical and noncanonical Wnt signaling pathways simultaneously through interaction with EZH2. These results show that HERES represents an early diagnostic and therapeutic target for squamous-cell-type cancers caused by defects in Wnt signaling pathways. Wnt signaling through both canonical and noncanonical pathways plays a core role in development. Dysregulation of these pathways often causes cancer development and progression. Although the pathways independently contribute to the core processes, a regulatory molecule that commonly activates both of them has not yet been reported. Here, we describe a long noncoding RNA (lncRNA), HERES, that epigenetically regulates both canonical and noncanonical Wnt signaling pathways in esophageal squamous cell carcinoma (ESCC). For this study, we performed RNA-seq analysis on Korean ESCC patients and validated these results on a larger ESCC cohort to identify lncRNAs commonly dysregulated in ESCCs. Six of the dysregulated lncRNAs were significantly associated with the clinical outcomes of ESCC patients and defined 4 ESCC subclasses with different prognoses. HERES reduction repressed cell proliferation, migration, invasion, and colony formation in ESCC cell lines and tumor growth in xenograft models. HERES appears to be a transacting factor that regulates CACNA2D3, SFRP2, and CXXC4 simultaneously to activate Wnt signaling pathways through an interaction with EZH2 via its G-quadruple structure-like motif. Our results suggest that HERES holds substantial potential as a therapeutic target for ESCC and probably other cancers caused by defects in Wnt signaling pathways.