Language

English

Publication Date

11-1-2024

Journal

Cancer Letters

DOI

10.1016/j.canlet.2024.217240

PMID

39265800

PMCID

PMC11471366

PubMedCentral® Posted Date

11-1-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

Nuclear Bcl-xL is found to promote cancer metastasis independently of its mitochondria-based anti-apoptotic activity. How Bcl-xL is translocated into the nucleus and how nuclear Bcl-xL regulates histone H3 trimethyl Lys4 (H3K4me3) modification have yet to be understood. Here, we report that C-terminal Binding Protein 2 (CtBP2) binds to 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 invasion and metastasis in mouse models. Furthermore, knockout of CtBP2 not only reduces the nuclear portion of Bcl-xL but also 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 the MLL1 enzymatic activity reverses Bcl-xL-induced H3K4me3 and TGFβ mRNA upregulation, as well as invasion. Moreover, the cleavage under targets and release using nuclease (CUT&RUN) assay coupled with next-generation sequencing reveals that H3K4me3 modifications are particularly enriched in the promotor regions of genes encoding TGFβ and its signaling pathway members in cancer cells overexpressing Bcl-xL. Altogether, the metastatic function of Bcl-xL is mediated by its interaction with CtBP2 and MLL1 and this study offers new therapeutic strategies to treat Bcl-xL-overexpressing cancer.

Keywords

bcl-X Protein, Humans, Animals, Alcohol Oxidoreductases, Mice, Co-Repressor Proteins, Epigenesis, Genetic, Cell Nucleus, Histones, Cell Line, Tumor, Nerve Tissue Proteins, Myeloid-Lymphoid Leukemia Protein, Histone-Lysine N-Methyltransferase, Neoplasm Metastasis, Gene Expression Regulation, Neoplastic, Female, Bcl-xL, CtBP2, H3K4me3, metastasis, epigenetic modification

Published Open-Access

yes

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