Bo-Hyun You^a,1, Jung-Ho Yoon^b,1, Hoin Kang^c, Eun Kyung Lee^c, Sang Kil Lee^b,d,2, and Jin-Wu Nam^a,e,2

^a Department of Life Science, College of Natural Sciences, Hanyang University, 04763 Seoul, Republic of Korea; ^b Division of Gastroenterology, Department of Internal Medicine, Yonsei Institute of Gastroenterology, Yonsei University College of Medicine, 03722 Seoul, Republic of Korea; ^c Department of Biochemistry, College of Medicine, The Catholic University of Korea, 06591 Seoul, Republic of Korea; ^d Brain Korea 21 PLUS Project for Medical Science, Yonsei University, 03722 Seoul, Republic of Korea; and ^e Research Institute for Convergence of Basic Sciences, Hanyang University, 04763 Seoul, Republic of Korea

¹ B.-H.Y. and J.-H.Y. contributed equally to this work.
² To whom correspondence may be addressed.

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.

epigenetic regulation, long noncoding RNA, Wnt signaling pathway, esophageal squamous cell carcinoma