Upregulation of the long noncoding RNA FOXD2-AS1 promotes carcinogenesis by epigenetically silencing EphB3 through EZH2 and LSD1, and predicts poor prognosis in gastric cancer

• Published in: Oncogene Vol. 37; no. 36; pp. 5020 - 5036
• Main Authors: Xu, Tong-peng, Wang, Wen-yu, Ma, Pei, Shuai, You, Zhao, Kun, Wang, Yan-fen, Li, Wei, Xia, Rui, Chen, Wen-ming, Zhang, Er-bao, Shu, Yong-qian
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2018; Nature Publishing Group
• Subjects: 13/1; 13/31; 13/44; 13/51; 13/89; 14/1; 38/39; 38/47; 38/77; 631/67; 692/53; 692/53/2422; Antisense RNA; Apoptosis; Cancer; Carcinogenesis; Cell Biology; Cell cycle; DNA; DNA biosynthesis; DNA replication; Gastric cancer; Gene expression; Gene set enrichment analysis; Genes; Genetic aspects; Human Genetics; Internal Medicine; Lysine; Medicine; Medicine & Public Health; Oncology; Prognosis; Protein binding; Proteins; Ribonucleic acid; RNA; Stomach cancer; Tumorigenesis; Tumors; Up-regulation
• ISSN: 0950-9232; 1476-5594; 1476-5594
• DOI: 10.1038/s41388-018-0308-y

Accumulating data indicate that long noncoding RNAs (lncRNAs) serve as important modulators in biological processes and are dysregulated in diverse tumors. The function of FOXD2-AS1 in gastric cancer (GC) progression and related biological mechanisms remain undefined. A comprehensive analysis identified that FOXD2-AS1 enrichment was upregulated markedly in GC and positively correlated with a large tumor size, a later pathologic stage, and a poor prognosis. Gene-set enrichment analysis (GSEA) in GEO datasets uncovered that cell cycle and DNA replication associated genes were enriched in patients with high FOXD2-AS1 expression. Loss of FOXD2-AS1 function inhibited cell growth via inhibiting the cell cycle in GC, whereas upregulation of FOXD2-AS1 expression promoted cancer progression. The enhancer of zeste homolog 2 (EZH2) and lysine (K)-specific demethylase 1A (LSD1) proteins were found to serve as binding partners of FOXD2-AS1 and mediators of FOXD2-AS1 function. Mechanically, FOXD2-AS1 promoted GC tumorigenesis partly through EZH2 and LSD1 mediated EphB3 downregulation. The present results revealed that FOXD2-AS1 acted as a tumor inducer in GC partly through EphB3 inhibition by direct interaction with EZH2 and LSD1, and may prove to be a potential biomarker of carcinogenesis.