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 rol...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 progres-sion 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 allevi-ated 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.Further-more,UBE2G2 inhibits oncogenic phenotypes by inactivating intracellular PI3K/AKT signaling and re-programming the tumor microenvironment.Therefore,targeting intercellular and intracellular molecular mechanisms of the hypoxiaeUBE2G2eLGALS3BP axis may contribute to developing various therapeu-tic strategies for UM.展开更多
基金supported by the National Natural Science Foundation of China(Nos.82273159 and 82171838)the Jiangsu Province’s Science and Technology Project(No.BE2020722,China).
文摘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 progres-sion 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 allevi-ated 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.Further-more,UBE2G2 inhibits oncogenic phenotypes by inactivating intracellular PI3K/AKT signaling and re-programming the tumor microenvironment.Therefore,targeting intercellular and intracellular molecular mechanisms of the hypoxiaeUBE2G2eLGALS3BP axis may contribute to developing various therapeu-tic strategies for UM.
