MESP2 binds competitively to TCF4 to suppress gastric cancer progression by regulating the SKP2/p27 axis

Gastric cancer (GC) is a major cause of human deaths worldwide, and is notorious for its high incidence and mortality rates. Mesoderm Posterior Basic Helix-loop-helix (bHLH) transcription factor 2 (MESP2) acts as a transcription factor with a conserved bHLH domain. However, whether MESP2 contributes to tumorigenesis and its potential molecular mechanisms, remain unexplored. Noticeably, MESP2 expression levels are decreased in GC tissues and cell lines compared to those in normal tissue. Further, in vitro and in vivo experiments have confirmed that MESP2 overexpression suppresses GC cell growth, migration, and invasion, whereas MESP2 knockdown results in the exact opposite. Here, we present the first report that MESP2 binds to transcription factor 7-like 2 (TCF7L2/TCF4) to inhibit the activation of the TCF4/beta-catenin transcriptional complex, decrease the occupancy of the complex on the S-phase kinase Associated Protein 2 (SKP2) promoter, and promote p27 accumulation. MESP2 knockdown facilitated tumorigenesis, which was partially suppressed by SKP2 knockdown. Taken together, we conclude that MESP2 binds competitively to TCF4 to suppress GC progression by regulating the SKP2/p27 axis, thus offering a potential therapeutic strategy for future treatment.