LncRNA HOXA11 AS Promotes Proliferation and Invasion of Gastric Cancer by Scaffolding the Chromatin Modification Factors PRC2, LSD1, and DNMT1.
Long noncoding RNAs (lncRNA) have been implicated in human cancer but their mechanisms of action are mainly undocumented. In this study, we investigated lncRNA alterations that contribute to gastric cancer through an analysis of The Cancer Genome Atlas RNA sequencing data and other publicly available microarray data. Here we report the gastric cancer associated lncRNA HOXA11 AS as a key regulator of gastric cancer development and progression. Patients with high HOXA11 AS expression had a shorter survival and poorer prognosis. In vitro and in vivo assays of HOXA11 AS alterations revealed a complex integrated phenotype affecting cell growth, migration, invasion, and apoptosis. Strikingly, high throughput sequencing analysis after HOXA11 AS silencing highlighted alterations in cell proliferation and cell cell adhesion pathways. Mechanistically, EZH2 along with the histone demethylase LSD1 or DNMT1 were recruited by HOXA11 AS, which functioned as a scaffold. HOXA11 AS also functioned as a molecular sponge for miR 1297, antagonizing its ability to repress EZH2 protein translation. In addition, we found that E2F1 was involved in HOXA11 AS activation in gastric cancer cells. Taken together, our findings support a model in which the EZH2/HOXA11 AS/LSD1 complex and HOXA11 AS/miR 1297/EZH2 cross talk serve as critical effectors in gastric cancer tumorigenesis and progression, suggesting new therapeutic directions in gastric cancer. Cancer Res; 76(21) 6299 310. (c)2016 AACR.
Cancer research