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

## TL;DR

This study shows how the ERRα-KDM5C complex controls STING activity to influence breast cancer growth through interferon signaling.

## Contribution

The study reveals a novel regulatory mechanism where ERRα-KDM5C suppresses STING enhancer activity to modulate interferon signaling in breast cancer.

## Key findings

- ERRα and KDM5C co-occupy enhancers, including the STING locus, to regulate enhancer activity.
- ERRα depletion activates STING signaling, increasing interferon and ISG expression.
- ERRα suppression reduces breast tumor growth via STING signaling activation.

## 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.

ERRα interacts with KDM5C to co-occupy active enhancers, including the locus of STING.ERRα depletion induces STING enhancer hyperactivation through KDM5C displacement and H3K4me3 deposition.STING-TBK1-IRF3 signaling activation mediates enhanced type I IFN/ISG expression upon ERRα depletion.ERRα contributes to breast tumor cell growth in vitro and in vivo, and our in vitro evidence indicates this occurs in part through suppression of STING signaling.

ERRα interacts with KDM5C to co-occupy active enhancers, including the locus of STING.

ERRα depletion induces STING enhancer hyperactivation through KDM5C displacement and H3K4me3 deposition.

STING-TBK1-IRF3 signaling activation mediates enhanced type I IFN/ISG expression upon ERRα depletion.

ERRα contributes to breast tumor cell growth in vitro and in vivo, and our in vitro evidence indicates this occurs in part through suppression of STING signaling.