NELFA-mediated pausing restrains YAP transcription and context-dependent outcomes in breast cancer

Introduction: The Hippo pathway effector YAP signaling is frequently dysregulated in cancer, promoting transcriptional programs linked to tumor progression. However, how general transcriptional control mechanisms intersect with YAP activity remains unclear. Methods: We investigated the role of NELFA, a component of promoter-proximal pausing (PPP), using genetic perturbation in HEK293T cells and MDA-MB-231. Transcriptomic profiling and analysis of three independent breast cancer cohorts were performed to assess clinical relevance. Results: NELFA depletion resulted in selective amplification of YAP-dependent transcription in HEK293T and MDA-MB-231. Gene expression analyses showed enrichment of YAP targets alongside epithelial-mesenchymal transition and TGF-β signaling-associated programs. Clinically, low NELFA expression correlated with poorer disease-free survival in YAP-high tumors, specifically in triple-negative breast cancer. Discussion: These findings identify PPP as a conserved regulatory layer modulating YAP-driven oncogenic transcription. Loss of NELFA may enhance oncogenic transcriptional programs specifically in TNBC, highlighting its potential relevance as a context-dependent biomarker in aggressive breast cancer subtypes.