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UNCX/SIN3A-Mediated H4K8 decrotonylation suppresses FOXO3 to drive TNBC progression and docetaxel resistance.

Songfu Shi·Dong Yan·Lixin Zhao·Yihao Zheng·Lingxi Ye·Yongjia Zeng·Linghang Zeng·Fan Wang·Wenjuan Wang·Shumeng Liu
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Abstract

Triple-negative breast cancer (TNBC) remains a clinically challenging subtype characterized by aggressive behavior and limited treatment options. Though docetaxel remains a cornerstone chemotherapy for TNBC, the frequent emergence of resistance highlights the urgent need to identify novel therapeutic targets. In this study, we report that uncoordinated homeobox (UNCX) is upregulated in docetaxel-resistant breast cancer cells, genomically amplified in breast cancer, and associated with poor survival in breast carcinoma patients. Functional studies revealed that UNCX promotes breast cancer cell proliferation, migration and reduces the docetaxel sensitivity. Mechanistically, UNCX functions as a transcriptional repressor by recruiting the SIN3A complex. Genome-wide profiling indicated that the UNCX/SIN3A complex directly binds to the promoters of tumor-suppressor genes including FOXO3, and represses their transcription by removing histone H4K8 crotonylation (H4K8cr). Additionally, the UNCX/SIN3A complex enhances FOXO3 phosphorylation and inhibits its nuclear translocation, further inhibiting its activity. Notably, SIN3A knockdown, FOXO3 overexpression, or crotonylation restoration effectively reverses UNCX-induced malignant phenotypes. These findings collectively establish the UNCX/SIN3A-H4K8cr-FOXO3 axis as a pivotal epigenetic regulator of TNBC progression and chemoresistance, revealing new avenues for targeted therapeutic development against this aggressive breast cancer subtype.

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HumansForkhead Box Protein O3HistonesDrug Resistance, NeoplasmDocetaxelFemaleTriple Negative Breast NeoplasmsCell Line, TumorRepressor ProteinsAnimalsDisease ProgressionCell ProliferationSin3 Histone Deacetylase and Corepressor ComplexGene Expression Regulation, NeoplasticHomeodomain ProteinsDocetaxel resistanceFOXO3Histone crotonylationTNBCUNCXJournal Article

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Songfu Shi, Dong Yan, Lixin Zhao, Yihao Zheng, Lingxi Ye, Yongjia Zeng, Linghang Zeng, Fan Wang, Wenjuan Wang, Shumeng Liu. 2026-08-12. UNCX/SIN3A-Mediated H4K8 decrotonylation suppresses FOXO3 to drive TNBC progression and docetaxel resistance.. https://doi.org/10.1016/j.cellsig.2026.112817

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Journal Article resourceAnimals subjectCell Line, Tumor subjectCell Proliferation subjectFemale subjectGene Expression Regulation, Neoplastic subjectHumans subjectJournal Article subjectdisease progression subject

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