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Updated: Aug 14, 2026

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06:44

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Published on: September 8, 2017

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

Songfu Shi1, Dong Yan2, Lixin Zhao1

  • 1Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China.

Cellular Signalling
|August 12, 2026
PubMed

Insights

Uncoordinated homeobox (UNCX) drives triple-negative breast cancer (TNBC) progression and docetaxel resistance by epigenetically silencing tumor suppressors. Targeting the UNCX/SIN3A axis offers a novel therapeutic strategy for TNBC.

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • Triple-negative breast cancer (TNBC) presents significant clinical challenges due to aggressive behavior and limited treatment options.
  • Docetaxel is a key chemotherapy for TNBC, but acquired resistance necessitates identifying novel therapeutic targets.
  • Uncoordinated homeobox (UNCX) has emerged as a potential factor in cancer progression and drug resistance.

Purpose of the Study:

  • To investigate the role of UNCX in TNBC chemoresistance and identify its underlying molecular mechanisms.
  • To explore the potential of targeting the UNCX pathway for therapeutic intervention in TNBC.

Main Methods:

  • Analysis of UNCX expression in docetaxel-resistant breast cancer cells and patient data.
  • Functional assays assessing the impact of UNCX on cancer cell proliferation, migration, and docetaxel sensitivity.
  • Mechanistic studies involving SIN3A complex recruitment, genome-wide profiling, and analysis of histone modifications (H4K8cr) and FOXO3 activity.
  • In vivo validation of therapeutic strategies including SIN3A knockdown, FOXO3 overexpression, and crotonylation restoration.

Main Results:

  • UNCX is upregulated in docetaxel-resistant cells, genomically amplified in breast cancer, and linked to poor patient survival.
  • UNCX overexpression promotes TNBC cell proliferation and migration while decreasing sensitivity to docetaxel.
  • UNCX recruits the SIN3A complex to repress transcription of tumor suppressor genes like FOXO3 by removing H4K8cr and inhibiting FOXO3 activity.
  • Restoring H4K8cr or enhancing FOXO3 function reverses UNCX-driven malignant phenotypes.

Conclusions:

  • The UNCX/SIN3A-H4K8cr-FOXO3 axis is a critical epigenetic regulator of TNBC progression and chemoresistance.
  • Targeting this axis presents a promising therapeutic avenue for overcoming docetaxel resistance in TNBC.
  • UNCX represents a novel therapeutic target for aggressive breast cancer subtypes.
Keywords:
Docetaxel resistanceFOXO3Histone crotonylationTNBCUNCX

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