UBE2G2 inhibits vasculogenic mimicry and metastasis of uveal melanoma by promoting ubiquitination of LGALS3BP

Uveal melanoma (UM) poses a significant lethality, with approximately 50% of those developing metastases surviving less than one year. In the progression of UM, vasculogenic mimicry (VM) induced by hypoxia plays a pivotal role, which also partially explains the resistance of UM to anti-angiogenic th...

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Published in:Acta pharmaceutica Sinica. B 2024-12, Vol.14 (12), p.5201-5218
Main Authors: Zhao, Andi, Zhou, Chenyu, Li, Jinjing, Wang, Zijin, Zhu, Hui, Shen, Shiya, Shao, Qing, Gong, Qi, Liu, Hu, Chen, Xuejuan
Format: Article
Language:English
Subjects:
Hypoxia
Invasion and metastasis
LGALS3BP
Original
Tumor microenvironment
UBE2G2
Ubiquitination
Uveal melanoma
Vasculogenic mimicry
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Summary:Uveal melanoma (UM) poses a significant lethality, with approximately 50% of those developing metastases surviving less than one year. In the progression of UM, vasculogenic mimicry (VM) induced by hypoxia plays a pivotal role, which also partially explains the resistance of UM to anti-angiogenic therapies. Nevertheless, the crucial molecular mechanisms underlying VM in the progression of UM remain unclear. We identified ubiquitin conjugating enzyme E2 G2 (UBE2G2) as a critical suppressor through transcriptomic sequencing and metastasis correlation screening. In UM, hypoxia-induced VM and metastasis are markedly exacerbated by UBE2G2 knockdown and significantly alleviated by its overexpression. Mechanistically, UBE2G2 directly binds to galectin 3 binding protein (LGALS3BP) and forms a complex with the E3 ubiquitin ligase tripartite motif containing 38 (TRIM38), facilitating ubiquitination-mediated degradation of LGALS3BP at the K104 residue. Furthermore, UBE2G2 inhibits oncogenic phenotypes by inactivating intracellular PI3K/AKT signaling and reprogramming the tumor microenvironment. Therefore, targeting intercellular and intracellular molecular mechanisms of the hypoxia–UBE2G2–LGALS3BP axis may contribute to developing various therapeutic strategies for UM. This study demonstrated that targeting both intercellular and intracellular molecular mechanisms of the hypoxia–UBE2G2–LGALS3BP axis may contribute to developing various therapeutic strategies for uveal melanoma. [Display omitted]
ISSN:2211-3835
2211-3843
DOI:10.1016/j.apsb.2024.09.005