Ge Lingjun, Zhao Gaichao, Lan Chao, Song Houji, Qi Dan, Huang Pan, Ke Xiaoxue, Cui Hongjuan
State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, 400716, China.
Cancer Center, Medical Research Institute, Southwest University, Chongqing, 400716, China.
Cell Death Discov. 2023 Mar 1;9(1):79. doi: 10.1038/s41420-023-01367-4.
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.
胃癌（GC）是全球人类死亡的主要原因，以其高发病率和死亡率而臭名昭著。中胚层后部碱性螺旋-环-螺旋（bHLH）转录因子2（MESP2）作为一种具有保守bHLH结构域的转录因子发挥作用。然而，MESP2是否促进肿瘤发生及其潜在的分子机制仍未得到探索。值得注意的是，与正常组织相比，GC组织和细胞系中MESP2的表达水平降低。此外，体外和体内实验证实，MESP2过表达抑制GC细胞的生长、迁移和侵袭，而MESP2敲低则产生完全相反的结果。在此，我们首次报道MESP2与转录因子7样2（TCF7L2/TCF4）结合，抑制TCF4/β-连环蛋白转录复合物的激活，降低该复合物在S期激酶相关蛋白2（SKP2）启动子上的占有率，并促进p27的积累。MESP2敲低促进肿瘤发生，而SKP2敲低可部分抑制这种作用。综上所述，我们得出结论，MESP2通过调节SKP2/p27轴竞争性地与TCF4结合以抑制GC进展，从而为未来的治疗提供了一种潜在的治疗策略。
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