Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 24620-24629 |
| Number of pages | 10 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 116 |
| Issue number | 49 |
| DOIs | |
| Publication status | Published - 2019 Dec 3 |
Bibliographical note
Funding Information:ACKNOWLEDGMENTS. We thank all Bioinformatics and Genomics (BIG) lab members for critical reading and comments. The results shown here are in part based upon data generated by the TCGA Research Network: https:// www.cancer.gov/tcga. The TCGA and GTEx data used in this manuscript were obtained from the database of Genotypes and Phenotypes (dbGaP) through accession numbers phs000178.v10.p8 and phs000424.v6.p1, respectively. This work was supported by Korean Health Technology R&D Project, Ministry of Health and Welfare (HI15C3224) and by the Bio and Medical Technology Development Program and the Basic Science Research Program through the National Research Foundation (NRF), funded by the Ministry of Science and Information and Communication Technologies (ICT) (grant numbers 2017M3A9G8084539, 2017R1A2B4006316, and 2018R1A2B2003782).
Funding Information:
We thank all Bioinformatics and Genomics (BIG) lab members for critical reading and comments. The results shown here are in part based upon data generated by the TCGA Research Network: https:// www.cancer.gov/tcga. The TCGA and GTEx data used in this manuscript were obtained from the database of Genotypes and Phenotypes (dbGaP) through accession numbers phs000178.v10.p8 and phs000424.v6.p1, respectively. This work was supported by Korean Health Technology R&D Project, Ministry of Health and Welfare (HI15C3224) and by the Bio and Medical Technology Development Program and the Basic Science Research Program through the National Research Foundation (NRF), funded by the Ministry of Science and Information and Communication Technologies (ICT) (grant numbers 2017M3A9G8084539, 2017R1A2B4006316, and 2018R1A2B2003782).
Publisher Copyright:
© 2019 National Academy of Sciences. All rights reserved.
All Science Journal Classification (ASJC) codes
- General
