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

Zhang, T.; Li, S.; Tan, A. Y.; Na, J.; Chen, Z.; Damle, P.; Chen, X.; Choi, S.; Mishra, B.; Wang, D.; Grossman, S. R.; Jiang, X.; Li, Y.; Chen, Y.-T.; Xiang, J. Z.; Du, N.

doi:10.1101/2023.04.26.538373

bioRxiv · 10.1101/2023.04.26.538373

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

Zhang, T.·Li, S.·Tan, A. Y.·Na, J.·Chen, Z.·Damle, P.·Chen, X.·Choi, S.·Mishra, B.·Wang, D.·Grossman, S. R.·Jiang, X.·Li, Y.·Chen, Y.-T.·Xiang, J. Z.·Du, N.

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Abstract

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 TGF{beta} 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 TGF{beta} 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 TGF{beta} 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.

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Zhang, T., Li, S., Tan, A. Y., Na, J., Chen, Z., Damle, P., Chen, X., Choi, S., Mishra, B., Wang, D., Grossman, S. R., Jiang, X., Li, Y., Chen, Y.-T., Xiang, J. Z., Du, N.. 2023-04-28. Bcl-xL is translocated to the nucleus via CtBP2 to epigenetically promote metastasis. https://doi.org/10.1101/2023.04.26.538373

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