Bcl-xL is translocated to the nucleus via CtBP2 to epigenetically promote metastasis.

TitleBcl-xL is translocated to the nucleus via CtBP2 to epigenetically promote metastasis.
Publication TypeJournal Article
Year of Publication2023
AuthorsZhang T, Li S, Tan YAdrian, Na JHyungJoon, Chen Z, Damle P, Chen X, Choi S, Mishra B, Wang D, Grossman SR, Jiang X, Li Y, Chen Y-T, Xiang JZ, Du Y-CNancy
Date Published2023 Apr 28

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 MLL1 enzymatic activity reverses Bcl-xL-induced H3K4me3 and TGFβ mRNA upregulation as well as cell invasion. Moreover, cleavage under targets and release using nuclease (CUT&RUN) coupled with next generation sequencing reveals that H3K4me3 modifications are particularly enriched in the promotor region of genes encoding TGFβ and its signaling pathway in the cancer cells overexpressing Bcl-xL. Altogether, the metastatic function of Bcl-xL is mediated by its interaction with CtBP2 and MLL1.

Alternate JournalbioRxiv
PubMed ID37163116
PubMed Central IDPMC10168309
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