Chang Shanshan, Fu Xianli, Xiang Longquan, Yuan Yuqian, Xiao Siyu, Peng Lehua, Xie Xiaoya, Kang Xinyi, Feng Xianling, Ashktorab Hassan, Peng Yin, Jin Zhe, Zhang Xiaojing
Guangdong Provincial Key Laboratory of Genome Stability and Disease Prevention, Department of Pathology, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, People's Republic of China.
ShenZhen University General Hospita, Shenzhen University, Shenzhen, Guangdong, People's Republic of China.
J Biol Chem. 2025 Jul 21;301(9):110507. doi: 10.1016/j.jbc.2025.110507.
Circular RNAs play significant roles in the development and progression of various cancers through diverse mechanisms, including the translation of novel proteins. Ferroptosis, a recently identified form of cell death, is associated with tumorigenesis in several cancers; however, its pathological mechanisms in gastric cancer (GC) remain unclear. Here, we found that circTUBGCP3 expression was elevated in GC tissues compared with normal gastric tissues. Moreover, circTUBGCP3 can be translated into a previously undescribed protein, TUBGCP3-230aa. In vitro and in vivo functional analyses demonstrated that both circTUBGCP3 and TUBGCP3-230aa promote rapid GC cell proliferation, with TUBGCP3-230aa exerting independent biological effects. Enolase 1 (ENO1), a glycolytic enzyme, was identified as an interacting partner of TUBGCP3-230aa, leading to activation of the glycolytic pathway and inhibition of ferroptosis in GC cells in vitro and in vivo. Mechanistically, TUBGCP3-230aa stabilizes ENO1 through posttranslational regulation, thereby repressing ferroptosis. Together, our results identify circTUBGCP3 and TUBGCP3-230aa as potential biomarkers for GC and uncover a novel mechanism of ferroptosis regulation, which may represent a promising therapeutic target. Furthermore, our findings highlight a critical moonlighting function of ENO1 in GC and underscore its potential as a novel target for cancer therapy.
环状RNA通过多种机制在各种癌症的发生和发展中发挥重要作用，包括翻译新的蛋白质。铁死亡是一种最近发现的细胞死亡形式，与几种癌症的肿瘤发生有关；然而，其在胃癌（GC）中的病理机制仍不清楚。在这里，我们发现与正常胃组织相比，circTUBGCP3在GC组织中的表达升高。此外，circTUBGCP3可以翻译成一种以前未描述的蛋白质TUBGCP3-230aa。体外和体内功能分析表明，circTUBGCP3和TUBGCP3-230aa均促进GC细胞快速增殖，且TUBGCP3-230aa发挥独立的生物学效应。烯醇化酶1（ENO1）是一种糖酵解酶，被鉴定为TUBGCP3-230aa的相互作用伴侣，导致体外和体内GC细胞中糖酵解途径的激活和铁死亡的抑制。机制上，TUBGCP3-230aa通过翻译后调控使ENO1稳定，从而抑制铁死亡。总之，我们的结果确定circTUBGCP3和TUBGCP3-230aa为GC的潜在生物标志物，并揭示了一种新的铁死亡调控机制，这可能是一个有前景的治疗靶点。此外，我们的发现突出了ENO1在GC中的关键兼职功能，并强调了其作为癌症治疗新靶点的潜力。
