The relationship of EPB41L4A-AS2 with the clinicopathological features and prognosis of HNSCC patients was evaluated.EPB41L4A-AS2 may be involved in processes associated with the tumor-associated signaling pathway, especially the TGF-B signaling pathway. Low EPB41L4A-AS2 expression was determined,and overexpression of this gene inhibited cell migration and invasion in the EMT model. Moreover, EPB41L4A-AS2 suppressed TGFBR1 expression.A major mechanism of lncRNAs in regulating gene expression involves the interaction with Polycomb repressive complex 2 (PRC2), which catalyzes the trimethylation of histone H3 lysine 27 (H3K27me3) to repress the transcription of specific genes. Considering that the promoter region of TGFBR1 is rich in methylation, we hypothesized that EPB41L4A-AS2 plays a role in inducing the methylation of the TGFBR1 promoter. Competing endogenous RNA (ceRNA) is currently under intense study as a novel mechanism for lncRNA functions, which indicates that RNA transcripts communicate with one another by miRNA response elements.