High CLOCK expression was linked to worse breast cancer outcomes and immune evasion through NF-kappaB p65 acetylation and transcription.
Evidence
This mixed bioinformatics and in vitro breast cancer study analyzed circadian clock gene expression, TCGA immune features, drug resistance in CLOCK-overexpressing cells, and sh-CLOCK MCF-7 pathway validation.
Caveat
The mechanistic evidence is mainly cell-based and dataset-associated, so it does not prove clinical benefit from targeting CLOCK.
Simplified
BACKGROUND: Disruption of circadian rhythm (DCR) has been connected with breast cancer (BC) susceptibility; whereas it is unclear whether status of key clock genes could be used in predicting BC prognosis, tumor immune microenvironment, and immunotherapy responses.
RESULTS: Circadian clock genes demonstrate significant dysregulation in BC, where elevated CLOCK expression emerges as an independent prognostic factor strongly correlated with adverse clinical outcomes. CLOCK-overexpressing BC cells exhibit enhanced proliferative ability and strong resistance to chemotherapy drugs doxorubicin and gemcitabine. High CLOCK expression correlates with reduced CD8T cell infiltration and increased M2 macrophage polarization, consistent with increased immune checkpoint molecule expression in the TCGA BC dataset. Additionally, patients with high CLOCK expression display lower Tumor Immune Dysfunction and Exclusion (TIDE) score. Mechanistically, RNA-sequencing identified suppressed , TNF, MAPK pathways, and PD-L1 expression in sh-CLOCK MCF-7 cells. Subsequent in vitro validation demonstrated that CLOCK mediates NF-κB p65 acetylation at K56 site, potentiating its transcriptional activation of PD-L1, thereby facilitating immune evasion in BC. +
CONCLUSIONS: CLOCK functions as a critical prognostic biomarker in BC by promoting tumor proliferation, chemoresistance, and immune evasion. Mechanistically, CLOCK mediates NF-κB p65 acetylation to enhance PD-L1 transcription, promoting immune evasion in BC.
Key numbers
1.348
for
From analysis of TCGA BRCA dataset.
0.745
5-year OS prediction AUC
Based on multivariate Cox regression analysis.
lower TIDE scores
expression correlation
Correlates with immune evasion mechanisms in TCGA BC patients.
Full Text
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