Increasing evidence suggests that deregulated RNA splicing factors play critical roles in tumorigenesis;however,their specific involvement in colon cancer remains largely unknown.Here we report that the splicing facto...Increasing evidence suggests that deregulated RNA splicing factors play critical roles in tumorigenesis;however,their specific involvement in colon cancer remains largely unknown.Here we report that the splicing factor RBM25 is overexpressed in colon cancer,and this increased expression correlates with a poor prognosis of patients with colon cancer.Functionally,RBM25 ablation suppresses the growth of colon cancer cells both in vitro and in vivo.Mechanistically,our transcriptome-wide analysis of splicing events revealed that RBM25 regulates a large number of cancer-related alternative splicing events across the human genome in colon cancer.Particularly,RBM25 regulates the splicing of MNK2 by interacting with the poly G rich region in exon 14a,thereby inhibiting the selection of the proximal 3'splice site(ss),resulting in the production of the oncogenic short isoform,MNK2b.Knockdown of RBM25 leads to an increase in the MNK2a isoform and a decrease in the MNK2b isoform.Importantly,re-expression of MNK2b or blocking the 3′ss of the alternative exon 14a with ASO partially reverses the RBM25 knockdown mediated tumor suppression.Moreover,MNK2b levels were significantly increased in colon cancer tissues,which is positively correlated with the expression level of RBM25.Collectively,our findings uncover the critical role of RBM25 as a key splicing factor in colon cancer,suggesting its potential as a prognostic marker and therapeutic target.展开更多
MAP kinase-interacting kinase-2 (Mnk2) is one of the downstream kinasesactivated by MAP kinases. It phosphorylates the eukaryotic initiation factor 4E (elF4E), althoughthe role of elF4E phosphorylation and the role of...MAP kinase-interacting kinase-2 (Mnk2) is one of the downstream kinasesactivated by MAP kinases. It phosphorylates the eukaryotic initiation factor 4E (elF4E), althoughthe role of elF4E phosphorylation and the role of Mnk2 in the process of proteintranslation are notwell understood. Except for elF4E, other physiological substrates of Mnk2 are still unidentified. Tolook for these unidentified substrates and to reveal the physiological function of Mnk2, weperformed a yeast two-hybrid screening with Mnk2 as the bait. The results demonstrated Mnk2 couldinteract with VHL (von Hippel-Lindau tumor suppressor), Rbx1 (ring-box1) and Cul2 (Cullin2) proteinsin yeast cells. Furthermore, we validated the interaction between Mnk2 and VHL proteins inmammalian cells by co-immunoprecipitation analysis. Because the three proteins VHL, Rbx1 and Cul2are all components of the CBC^(VHL) ubiquitin ligase E3 complex, it has been shown that Mnk2 caninteract with CBC^(VHL) complex, and is probably one of the newsubstrates of the CBC^(VHL) complex.Furthermore, during the interaction of Mnk2 with von Hippel-Lindau (VHL) tumor suppressor- bindingprotein 1 (VBP1), it appears that Mnk2 also joins to modulate cell shape as VBP1 plays an importantrole in the process of the maturation of the cytoskeleton and in the process of morphogenesis.展开更多
基金supported by the National Key Research and Development Program of China(2022YFA1104002,2023YFE0117500)the National Natural Science Foundation of China(82225034,82273427)+1 种基金the Science and Technology Innovation Talent Support Program of Dalian(2022RJ15,2022JJ11CG009)the Liaoning Revitalization Talents Program(XLYC2202027)。
文摘Increasing evidence suggests that deregulated RNA splicing factors play critical roles in tumorigenesis;however,their specific involvement in colon cancer remains largely unknown.Here we report that the splicing factor RBM25 is overexpressed in colon cancer,and this increased expression correlates with a poor prognosis of patients with colon cancer.Functionally,RBM25 ablation suppresses the growth of colon cancer cells both in vitro and in vivo.Mechanistically,our transcriptome-wide analysis of splicing events revealed that RBM25 regulates a large number of cancer-related alternative splicing events across the human genome in colon cancer.Particularly,RBM25 regulates the splicing of MNK2 by interacting with the poly G rich region in exon 14a,thereby inhibiting the selection of the proximal 3'splice site(ss),resulting in the production of the oncogenic short isoform,MNK2b.Knockdown of RBM25 leads to an increase in the MNK2a isoform and a decrease in the MNK2b isoform.Importantly,re-expression of MNK2b or blocking the 3′ss of the alternative exon 14a with ASO partially reverses the RBM25 knockdown mediated tumor suppression.Moreover,MNK2b levels were significantly increased in colon cancer tissues,which is positively correlated with the expression level of RBM25.Collectively,our findings uncover the critical role of RBM25 as a key splicing factor in colon cancer,suggesting its potential as a prognostic marker and therapeutic target.
文摘MAP kinase-interacting kinase-2 (Mnk2) is one of the downstream kinasesactivated by MAP kinases. It phosphorylates the eukaryotic initiation factor 4E (elF4E), althoughthe role of elF4E phosphorylation and the role of Mnk2 in the process of proteintranslation are notwell understood. Except for elF4E, other physiological substrates of Mnk2 are still unidentified. Tolook for these unidentified substrates and to reveal the physiological function of Mnk2, weperformed a yeast two-hybrid screening with Mnk2 as the bait. The results demonstrated Mnk2 couldinteract with VHL (von Hippel-Lindau tumor suppressor), Rbx1 (ring-box1) and Cul2 (Cullin2) proteinsin yeast cells. Furthermore, we validated the interaction between Mnk2 and VHL proteins inmammalian cells by co-immunoprecipitation analysis. Because the three proteins VHL, Rbx1 and Cul2are all components of the CBC^(VHL) ubiquitin ligase E3 complex, it has been shown that Mnk2 caninteract with CBC^(VHL) complex, and is probably one of the newsubstrates of the CBC^(VHL) complex.Furthermore, during the interaction of Mnk2 with von Hippel-Lindau (VHL) tumor suppressor- bindingprotein 1 (VBP1), it appears that Mnk2 also joins to modulate cell shape as VBP1 plays an importantrole in the process of the maturation of the cytoskeleton and in the process of morphogenesis.
