2. Academic Validation
  3. ERRα-KDM5C restrains STING enhancer activity to modulate type I interferon signaling in breast cancer progression

ERRα-KDM5C restrains STING enhancer activity to modulate type I interferon signaling in breast cancer progression

  • Cell Death Dis. 2026 Feb 18;17(1):228. doi: 10.1038/s41419-026-08499-2.
Zu-Hui Xu # 1 2,  Jie Chen # 1 3,  Ying He # 4,  Cheng Lei 5 6 7,  Xiao-Ling Wang 1 2,  De-Fa Huang 1 2,  Zheng-Zhe Li 1,  Hui Zhou 1 2,  Mei-Yan Wang 8,  Cheng-Gui Song 8,  Juan Lin 9,  Wen Liu 10 11,  Xiao-Nan Wu 12 13,  Wen-Juan Zhang 14 15 16 17
Affiliations

Affiliations

  • 1 Department of Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China.
  • 2 School of Medical Technology, Gannan Medical University, Ganzhou, Jiangxi, China.
  • 3 Department of Laboratory Medicine, The Affiliated Yongchuan Hospital of Chongqing Medical University, Chongqing, China.
  • 4 Laboratory Animal Research Center, Xiamen University, Xiamen, Fujian, China.
  • 5 State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, China.
  • 6 Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, China.
  • 7 State Key Laboratory of Cellular Stress Biology, Cancer Research Center, School of Medicine, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, China.
  • 8 The First School of Clinical Medicine, Gannan Medical University, Ganzhou, Jiangxi, China.
  • 9 State Key Laboratory of Cellular Stress Biology, Cancer Research Center, School of Medicine, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, China. [email protected].
  • 10 State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, China. [email protected].
  • 11 Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, China. [email protected].
  • 12 State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, China. [email protected].
  • 13 Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, China. [email protected].
  • 14 Department of Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China. [email protected].
  • 15 School of Medical Technology, Gannan Medical University, Ganzhou, Jiangxi, China. [email protected].
  • 16 Precision Medicine Center, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China. [email protected].
  • 17 Ganzhou Key Laboratory of Immunotherapeutic Drugs Developing for Childhood Leukemia, Gannan Medical University, Ganzhou, Jiangxi, China. [email protected].
  • # Contributed equally.
PMID: 41708589 DOI: 10.1038/s41419-026-08499-2
Abstract

Regulation of enhancer activity plays a pivotal role in governing gene expression and cellular behaviors. However, the precise mechanisms underlying dynamic control of active enhancers remain incompletely defined. Here, we demonstrate that the nuclear receptor estrogen-related receptor α (ERRα) forms a functional complex with the H3K4me3-specific demethylase KDM5C to co-occupy a large set of active enhancers, including the locus of STING. In breast Cancer cells, ERRα depletion induces STING enhancer hyperactivation, evidenced by H3K4me3 deposition, decreased H3K4me1, and increased enhancer RNA (eRNA) transcription. Accordingly, depletion of ERRα leads to further activation of STING gene transcription and TBK1-IRF3 pathway, accompanied by increased type I interferon (IFN) and IFN-stimulated gene (ISG) expression, as confirmed by transcriptomic analysis. Notably, depleting ERRα markedly attenuates breast tumor cell growth in vitro and in vivo, and our in vitro evidence indicates this occurs in part through activating STING signaling. These findings establish that the ERRα-KDM5C serves as a critical checkpoint for STING enhancer activity, revealing a regulatory mechanism of STING enhancer activity in breast tumor progression.

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