biostudies-literatureUnknownZhang TBesides its mitochondria-based anti-apoptotic role, Bcl-xL also travels to the nucleus to promote cancer metastasis by upregulating global histone H3 trimethyl Lys4 (H3K4me3) and TGFβ transcription. How Bcl-xL is translocated into the nucleus and how nuclear Bcl-xL regulates H3K4me3 modification are not understood. Here, we report that C-terminal Binding Protein 2 (CtBP2) binds Bcl-xL via its N-terminus and translocates Bcl-xL into the nucleus. Knockdown of CtBP2 by shRNA decreases the nuclear portion of Bcl-xL and reverses Bcl-xL-induced cell migration and metastasis in mouse models. Furthermore, knockout of CtBP2 suppresses Bcl-xL transcription. The binding between Bcl-xL and CtBP2 is required for their interaction with MLL1, a histone H3K4 methyltransferase. Pharmacologic inhibition of bioRxiv : the preprint server for biology2023.04.26.538373https://www.ebi.ac.uk/biostudies/studies/S-EPMC10168309biostudies-literatureBcl-xL is translocated to the nucleus via CtBP2 to epigenetically promote metastasis.PMC10168309Grossman SRTan YAWang DChoi SLi YZhang TLi SChen ZMishra BChen YTJiang XDu YNDamle PChen XNa JHXiang JZfalseBcl-xL is translocated to the nucleus via CtBP2 to epigenetically promote metastasis.Besides its mitochondria-based anti-apoptotic role, Bcl-xL also travels to the nucleus to promote cancer metastasis by upregulating global histone H3 trimethyl Lys4 (H3K4me3) and TGFβ transcription. How Bcl-xL is translocated into the nucleus and how nuclear Bcl-xL regulates H3K4me3 modification are not understood. Here, we report that C-terminal Binding Protein 2 (CtBP2) binds Bcl-xL via its N-terminus and translocates Bcl-xL into the nucleus. Knockdown of CtBP2 by shRNA decreases the nuclear portion of Bcl-xL and reverses Bcl-xL-induced cell migration and metastasis in mouse models. Furthermore, knockout of CtBP2 suppresses Bcl-xL transcription. The binding between Bcl-xL and CtBP2 is required for their interaction with MLL1, a histone H3K4 methyltransferase. Pharmacologic inhibition of 2023-01-01T00:00:00Z2023 Apr2025-04-04T13:07:19.418Z2025-04-04T13:07:19.418ZS-EPMC101683093716311610.1101/2023.04.26.538373