College of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400016, China.
Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, 832002, China.
Cell Death Dis. 2024 Oct 10;15(10):740. doi: 10.1038/s41419-024-07137-z.
Esophageal squamous cell carcinoma (ESCC) is a common fatal malignant tumor of the digestive tract; however, its pathogenic mechanism is unknown and lacks specific molecular diagnosis and treatment. Therefore, it is particularly important to identify new tumor biomarkers to enhance the early diagnosis and molecular-targeted therapy of ESCC. Here, we found that the E3 ubiquitin ligase Tripartitemotif-containing33 (TRIM33) is highly expressed in ESCC tissues and cell lines, and is associated with adverse clinical outcomes. We determined that TRIM33 drives aerobic glycolysis to promote tumor growth in vivo and in vitro. In terms of mechanism, TRIM33 binds to p53 to inhibit its stability and promote the expression of downstream glycolysis target genes GLUT1, HK2, PKM2, and LDHA. In addition, TRIM33 promotes the polyubiquitination of P53 K48-linked and proteasome degradation. Further studies have shown that the K351 site of P53 is the key site mediating the ubiquitination of P53 K48-linked to promote aerobic glycolysis in ESCC and tumor cell growth. Our results reveal that the TRIM33-P53 signal axis regulates glycolysis during ESCC and may provide a new perspective for the diagnosis and treatment of ESCC.
食管鳞状细胞癌 (ESCC) 是一种常见的致命性消化道恶性肿瘤；然而，其发病机制尚不清楚，缺乏特异性的分子诊断和治疗方法。因此，鉴定新的肿瘤标志物对于提高 ESCC 的早期诊断和分子靶向治疗水平尤为重要。在这里，我们发现 E3 泛素连接酶 Tripartitemotif-containing33（TRIM33）在 ESCC 组织和细胞系中高表达，并与不良的临床结局相关。我们确定 TRIM33 通过有氧糖酵解驱动肿瘤在体内和体外的生长。在机制方面，TRIM33 与 p53 结合以抑制其稳定性并促进下游糖酵解靶基因 GLUT1、HK2、PKM2 和 LDHA 的表达。此外，TRIM33 促进 P53 K48 连接的多泛素化和蛋白酶体降解。进一步的研究表明，P53 的 K351 位点是介导 P53 K48 连接泛素化以促进 ESCC 和肿瘤细胞生长中有氧糖酵解的关键位点。我们的结果揭示了 TRIM33-P53 信号轴在 ESCC 期间调节糖酵解，可能为 ESCC 的诊断和治疗提供新视角。
