Transcription factor, E4BP4, inhibits autophagy and apoptosis in multiple myeloma and promotes the HDAC3-mediated suppression of the Beclin1 promoter to reducedexamethasone sensitivity

Sep 22, 2026

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Background: Multiple myeloma is a plasma cell malignancy prone to drug resistance, with unclear relationships between autophagy and apoptosis. This study investigated transcription factor E4BP4’s role in autophagy and apoptosis in MM. Methods: GEO and TCGA transcriptomic analyses assessed E4BP4 expression and clinical correlations. Experimental studies in U266 cells and PBMCs used western blotting, RT-qPCR, immunohistochemistry, and functional assays to quantify autophagy/apoptosis and dexamethasone response. Results: E4BP4 overexpression suppressed both autophagy and apoptosis, increased HDAC3 transcription, activated mTOR signaling, and reduced Beclin1 promoter activity, contributing to dexamethasone resistance. Conclusion: E4BP4 promotes MM progression and identifies E4BP4 as a potential therapeutic target.

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Li et al. Journal of Translational Medicine (2026) 24:806 [https://doi.org/10.1186/s12967-026-08345-1](https://doi.org/10.1186/s12967-026-08345-1) Journal of Translational Medicine RESEARCH Open Access Transcription factor, E4BP4, inhibits autophagy and apoptosis in multiple myeloma and promotes the HDAC3-mediated suppression of the Beclin1 promoter to reducedexamethasone sensitivity Licheng Li1,3†, Mengxing Li1,2,3*†, Honglin Liu4†, Ting Chen3, Wenxiu Yang5, Weiwei Cheng3, Zhongmin Kang3, Xueying Yang3, Ying Luo 1,2* and Qinshan Li 1,6,7* Abstract Background Multiple myeloma (MM) is a plasma cell malignancy prone to drug resistance, with unclear autophagy/ apoptosis interactions in its etiology. This study explored transcription factor E4BP4’s role in MM autophagy and apoptosis. Methods Transcriptomic data from GEO and TCGA assessed E4BP4 expression and clinicopathological correlations. E4BP4 expression in MM cell line U266 and normal PBMCs was analyzed via western blotting, RT-qPCR, and immunohistochemistry. Autophagy/apoptosis markers were measured using CCK-8, flow cytometry, electron microscopy, and immunofluorescence. Molecular docking identified E4BP4 DNA-binding sites. Co-immunoprecipitation, luciferase reporter assays, and ChIP-qPCR analyzed E4BP4 transcriptional activity. E4BP4 knockdown effects were tested in mouse xenografts. Results E4BP4 was overexpressed in MM tumor tissues versus non-cancerous tissues, and in U266 cells versus PBMCs. High E4BP4 suppressed apoptosis and autophagy in MM cells. E4BP4 overexpression upregulated HDAC3 transcription, activated mTOR signaling, and reduced H3K9Ac/H3K27Ac association with Beclin1 promoter, decreasing Beclin1 expression. E4BP4 overexpression reduced U266 sensitivity to dexamethasone, while knockdown enhanced †Licheng Li, Mengxing Li and Honglin Liu contributed equally to this study. *Correspondence: Mengxing Li[lmx1234@gmc.edu.cn](lmx1234@gmc.edu.cn)[ ](lmx1234@gmc.edu.cn)Ying Luo [luoying@gmc.edu.cn](luoying@gmc.edu.cn)[ ](luoying@gmc.edu.cn)Qinshan Li[liqinshan@gmc.edu.cn](liqinshan@gmc.edu.cn) Full list of author information is available at the end of the article © The Author(s) 2026, modified publication 2026. Open Access This article is licensed under a Creative Commons Attribution-NonCommercialNoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://cre](http://cre)[ativecommons.org/licenses/by-nc-nd/4.0/](ativecommons.org/licenses/by-nc-nd/4.0/.)[.](ativecommons.org/licenses/by-nc-nd/4.0/.) Li et al. Journal of Translational Medicine (2026) 24:806 Page 2 of 23 drug sensitivity. E4BP4 knockdown inhibited U266 xenograft growth in mice, with combined knockdown and dexamethasone yielding additive effects. Conclusion E4BP4 promotes MM progression by upregulating HDAC3, reducing histone acetylation and Beclin1 transcription to suppress autophagy/apoptosis. Its role in dexamethasone resistance highlights E4BP4 as a potential therapeutic target. Keywords Autophagy, E4BP4, HDAC3, Dexamethasone, Multiple myeloma Background Multiple myeloma (MM) is a hematological malignancy characterized by the clonal proliferatio

FAQs

What role does E4BP4 play in multiple myeloma progression?

E4BP4 is overexpressed in multiple myeloma tissues and cells and promotes disease progression by suppressing autophagy/apoptosis and activating downstream survival-related signaling.

How does E4BP4 affect autophagy and apoptosis in MM cells?

High E4BP4 suppresses apoptosis and autophagy in MM cells. It reduces Beclin1 expression through transcriptional regulation linked to histone acetylation changes.

How is E4BP4 linked to dexamethasone sensitivity?

E4BP4 overexpression reduces U266 sensitivity to dexamethasone, while E4BP4 knockdown enhances drug sensitivity. Combined knockdown and dexamethasone show additive effects in xenograft models.

Sep 22, 2026

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