TRIM49 Deficiency Stabilizes a Galectin-3/EGR1 Transcriptional Complex That Drives Invasiveness of Gastric Adenocarcinoma

作者：Zhong‐yi Qin, Linrong Che, Shuoran Tian, Xianfeng Li, Xiang-yu Du, Jinyang Li, Qin Liu, Ke-wei Liu, Zhaole Chu, Mengyi Han, Xu Chen, L.-Y. Wu, Sen Yang, Chenhui Wang, Y Deng, Xiaohan Wang, Deshun Zeng, X Zhang, Min Mao, Qingning Zhao, Jingyuan Li, Hong Zhou, Liting Shen, Shiyin Peng, Ning Li, Dongfeng Chen, Liangzhi Wen, Qiaoqiao Zhang, Ke Li, Tao Wang, Junyu Xiang, Xiu‐Wu Bian, Bin Wang · 发表于：Cancer Research · 年份：2025 · DOI：10.1158/0008-5472.can-25-0252 · 被引用次数：5 · 研究领域：Galectins and Cancer Biology、interferon and immune responses、Cancer Mechanisms and Therapy

Tissue invasion is an initiating step of the cancer metastatic cascade. Unraveling the mechanisms underlying intracellular signaling pathway rewiring that activates downstream transcriptional machinery to drive invasiveness could help identify improved strategies to prevent and treat metastasis. Through an unbiased genome-wide CRISPR screen in a mouse model of gastric adenocarcinoma (GAC), an E3 ubiquitin ligase, tripartite motif-containing protein 49 (TRIM49), was identified as a potent suppressor of cancer invasiveness. In two thirds of GAC, TRIM49 expression was downregulated in invading cancer cells, in which TRIM49 deficiency correlated with deeper tumor infiltration and lymph node metastasis and was indicative of shorter overall patient survival. In multiple orthotopic GAC mouse models, TRIM49-deficient cancer cells were highly infiltrative, leading to multiorgan metastasis. Mechanistically, galectin-3, a putative regulator of cancer invasion, was stabilized in TRIM49-deficient cancer, largely because of the failure to undergo TRIM49-mediated polyubiquitination and proteasomal degradation. Consequently, galectin-3 assembled a complex with EGR1, thereby regulating transcriptional activities of a proinvasive gene module. As the galectin-3/EGR1 complex acted as a key node relaying proinvasive signaling, its disruption using GB1107, an oral galectin-3 inhibitor, suppressed tissue infiltration and metastasis of patient-derived xenografts. Taken together, a proinvasive galect...