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Abstract：
Ubiquitination plays a pivotal regulatory role in tumor progression. Among the components of the ubiquitin-proteasome system (UPS), ubiquitin-protein ligase E3 has emerged as a key molecule. Nevertheless, the biological functions of E3 ubiquitin ligases and their potential mechanisms orchestrating glycolysis in gastric cancer (GC) remain to be elucidated. In this study, we conducted a comprehensive transcriptomic analysis to identify the core E3 ubiquitin ligases in GC, followed by extensive validation of the expression patterns and clinical significance of Tripartite motif-containing 50 (TRIM50) both in vitro and in vivo. Remarkably, we found that TRIM50 was downregulated in GC tissues, associated with malignant progression and poor patient survival. Functionally, overexpression of TRIM50 suppressed GC cell proliferation and indirectly mitigated the invasion and migration of GC cells by inhibiting the M2 polarization of tumor-associated macrophages (TAMs). Mechanistically, TRIM50 inhibited the glycolytic pathway by ubiquitinating Phosphoglycerate Kinase 1 (PGK1), thereby directly suppressing GC cell proliferation. Simultaneously, the reduction in lactate led to diminished M2 polarization of TAMs, indirectly inhibiting the invasion and migration of GC cells. Notably, the downregulation of TRIM50 in GC was mediated by the METTL3/YTHDF2 axis in an m6A-dependent manner. In our study, we definitively identified TRIM50 as a tumor suppressor gene (TSG) that effectively inhibits glycolysis and the malignant progression of GC by ubiquitinating PGK1, thus offering novel insights and promising targets for the diagnosis and treatment of GC.
摘要：
泛素化在肿瘤进展中起着关键的调节作用。在泛素-蛋白酶体系统（UPS）的组成部分中，泛素蛋白连接酶E3已成为关键分子。然而，E3泛素连接酶的生物学功能及其在胃癌（GC）中协调糖酵解的潜在机制仍有待阐明。在这项研究中,我们进行了全面的转录组学分析，以确定GC中的核心E3泛素连接酶，随后在体外和体内广泛验证了含三方基序50（TRIM50）的表达模式和临床意义。值得注意的是,我们发现TRIM50在GC组织中下调，与恶性进展和患者生存率低相关。功能上,TRIM50的过表达通过抑制肿瘤相关巨噬细胞（TAMs）的M2极化，抑制GC细胞增殖，间接减轻GC细胞的侵袭和迁移。机械上,TRIM50通过泛素化磷酸甘油酸激酶1（PGK1）抑制糖酵解途径，从而直接抑制GC细胞增殖。同时,乳酸的减少导致TAMs的M2极化减少，间接抑制GC细胞的侵袭和迁移。值得注意的是,GC中TRIM50的下调由METTL3/YTHDF2轴以m6A依赖性方式介导.在我们的研究中,我们确定TRIM50是一种肿瘤抑制基因(TSG),它通过泛素化PGK1有效抑制糖酵解和GC的恶性进展,从而为GC的诊断和治疗提供了新的见解和有希望的靶点.
