TRIM24 drives colorectal cancer progression via CAVIN2 degradation and ERK/RhoA pathway activation

作者：Wen Cai, Yaoyao Zhong, Junwei Zhao, Jianmei Mao, Lu Hua, Xin He, Hanguang Hu, Jianshan Mao, Shu Zheng, Weiting Ge, Jiawei Zhang · 发表于：Cell investigation. · 年份：2025 · DOI：10.1016/j.clnves.2025.100033 · 被引用次数：3 · 研究领域：Signaling Pathways in Disease、interferon and immune responses、Caveolin-1 and cellular processes

Microsatellite‐stable (MSS) colorectal cancer (CRC), which constitutes the majority of advanced cases, has a dismal prognosis and is largely refractory to immune checkpoint inhibitors, while rapidly acquiring resistance to targeted therapies. Here, we identified TRIM24 as a critical oncoprotein driving MSS CRC progression. TRIM24 was overexpressed in tumors and correlated with adverse outcomes in MSS stage III CRC. Functional assays both in vitro and in vivo demonstrated that TRIM24 was essential for CRC cell proliferation, migration, invasion, and metastasis. Mechanistically, TRIM24 acted as an E3 ubiquitin ligase to catalyze K78‐linked polyubiquitination of the tumor suppressor CAVIN2, targeting it for proteasomal degradation. CAVIN2 Loss dismantled its scaffolding of the phosphatase PPP1CA, leading to sustained ERK and RhoA phosphorylation and downstream oncogenic signaling. These mechanistic insights, supported by survival analyses in TCGA and an independent MSS CRC cohort, revealed a novel TRIM24-CAVIN2-PPP1CA axis and underscored TRIM24 as a promising therapeutic target to address the unmet needs in MSS CRC treatment. • TRIM24 deletion impairs CRC cell proliferation, migration, invasion, and metastasis in vitro and in vivo . • TRIM24′s RBCC domain promotes K78-linked polyubiquitination of CAVIN2, leading to its proteasomal degradation. • CAVIN2 loss disrupts PPP1CA scaffolding, sustaining ERK/RhoA activity and driving oncogenic signaling. • The novel TRIM24–CAVIN2–PPP1C...