Bcl-xL is translocated to the nucleus via CtBP2 to epigenetically promote metastasis Journal Article
| Authors: | Zhang, T.; Li, S.; Tan, Y. A.; Chen, X.; Zhang, C.; Chen, Z.; Mishra, B.; Na, J. H.; Choi, S.; Shin, S. J.; Damle, P.; Chougoni, K. K.; Grossman, S. R.; Wang, D.; Jiang, X.; Li, Y.; Hissong, E.; Chen, Y. T.; Xiang, J. Z.; Du, Y. C. N. |
| Article Title: | Bcl-xL is translocated to the nucleus via CtBP2 to epigenetically promote metastasis |
| 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. © 2024 Elsevier B.V. |
| Keywords: | immunohistochemistry; signal transduction; controlled study; protein expression; unclassified drug; human cell; nonhuman; polymerase chain reaction; mass spectrometry; animal cell; mouse; animal tissue; gene overexpression; metastasis; ovary cancer; breast cancer; gene amplification; confocal microscopy; transforming growth factor beta; cell line; animal experiment; animal model; caspase 3; immunofluorescence; in vitro study; enzyme activity; protein bcl xl; prostate cancer; epigenetics; membrane protein; western blotting; scoring system; fluorescence microscopy; cell fractionation; liver cancer; down regulation; upregulation; doxycycline; c terminal binding protein 2; genetic procedures; dna extraction; transient transfection; short hairpin rna; esophageal squamous cell carcinoma; epithelial mesenchymal transition; caspase 7; bcl-xl; high throughput sequencing; h3k4me3; epigenetic modification; gene knockdown; human; male; female; article; crispr-cas9 system; hek293t cell line; mll1 protein; mda-mb-231 cell line; u2os cell line; real time reverse transcription polymerase chain reaction; transwell assay; ctbp2; crosslinking immunoprecipitation; cut and run technique; n134 cell line |
| Journal Title: | Cancer Letters |
| Volume: | 604 |
| ISSN: | 0304-3835 |
| Publisher: | Elsevier Ireland Ltd. |
| Date Published: | 2024-11-01 |
| Start Page: | 217240 |
| Language: | English |
| DOI: | 10.1016/j.canlet.2024.217240 |
| PUBMED: | 39265800 |
| PROVIDER: | scopus |
| PMCID: | PMC11471366 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
