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

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.