Loss of ZNF408 attenuates STING-mediated immune surveillance in breast carcinogenesis.

Understanding the mechanism of cancer immune surveillance is crucial for precision medicine and effective immunotherapy. We report here that ZNF408, encoded by a gene linked to familial exudative vitreoretinopathy (FEVR) and autosomal recessive retinitis pigmentosa (RP), is physically associated with the SETD1A/COMPASS complex mediating histone H3 lysine 4 (H3K4) methylation in breast cancer cells. Integrative epigenomic and transcriptomic analyses reveal that ZNF408 and SETD1A share overlapped chromatin landscape and coordinately activate a cohort of genes, among which STING1 is critical in innate immune responses. ZNF408-SETD1A complex enhances STING1 expression and promotes STING-mediated anti-tumor immune responses both in vitro and in vivo. Importantly, ZNF408 expression is positively correlated with that of STING1 and negatively correlated with the histological grade of breast cancer. Our study uncovers a role for ZNF408 in cancer immune surveillance, supporting further investigations for therapeutic targeting of ZNF408-SETD1A-STING1 axis in breast carcinogenesis and other ZNF408-associated diseases including FEVR and RP.

PD-L1-mediated immune evasion in triple-negative breast cancer is linked to the loss of ZNF652.

The intrinsic regulation of programmed death ligand-1 (PD-L1) expression remains unclear. Here, we report that zinc-finger protein 652 (ZNF652) is a potent transcription repressor of PD-L1. ZNF652 frequently experiences loss of heterozygosity (LOH) in various cancers. Higher LOH rate and lack of estrogen-inducible transcription lead to suppressed expression of ZNF652 in triple-negative breast cancer (TNBC). Mechanistically, ZNF652 is physically associated with the NuRD transcription co-repressor complex to repress a cohort of genes, including PD-L1. Overexpression of ZNF652 inhibits PD-L1 transcription, whereas depletion of ZNF652 upregulates PD-L1. Loss of ZNF652 in TNBC unleashes PD-L1-mediated immune evasion both in vitro and in vivo. Significantly, ZNF652 expression is progressively lost during breast cancer progression, and a low ZNF652 level is correlated with elevated PD-L1 expression, less infiltrated CD8+ T cells, and poor prognosis in TNBC. Our study provides insights into PD-L1 regulation and supports the pursuit of ZNF652 as a potential biomarker and drug target for breast cancer immunotherapy.

RCCD1 promotes breast carcinogenesis through regulating hypoxia-associated mitochondrial homeostasis.

Regulator of chromosome condensation domain-containing protein 1 (RCCD1), previously reported as a partner of histone H3K36 demethylase KDM8 involved in chromosome segregation, has been identified as a potential driver for breast cancer in a recent transcriptome-wide association study. We report here that, unexpectedly, RCCD1 is also localized in mitochondria. We show that RCCD1 resides in the mitochondrial matrix, where it interacts with the mitochondrial contact site/cristae organizing system (MICOS) and mitochondrial DNA (mtDNA) to regulate mtDNA transcription, oxidative phosphorylation, and the production of reactive oxygen species. Interestingly, RCCD1 is upregulated under hypoxic conditions, leading to decreased generation of reactive oxygen species and alleviated apoptosis favoring cancer cell survival. We show that RCCD1 promotes breast cancer cell proliferation in vitro and accelerates breast tumor growth in vivo. Indeed, RCCD1 is overexpressed in breast carcinomas, and its level of expression is associated with aggressive breast cancer phenotypes and poor patient survival. Our study reveals an additional dimension of RCCD1 functionality in regulating mitochondrial homeostasis, whose dysregulation inflicts pathologic states such as breast cancer.