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 (GC) through an analysis of TCGA RNA sequencing data and other publicly available microarray data. Here we report the GC-associated lncRNA HOXA11-AS as a key regulator of GC 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 GC cells. Taken together, our findings support a model in which the EZH2/HOXA11-AS/LSD1 complex and HOXA11-AS/miR-1297/EZH2 crosstalk serve as critical effectors in GC tumorigenesis and progression, suggesting new therapeutic directions in gastric cancer.