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NELFA-mediated promoter-proximal pausing restrains YAP-driven transcription and shapes context-dependent outcomes in breast cancer

ABSTRACT: Overexpression of YAP is associated with oncogenesis and tumor progression in multiple malignancies. YAP is the key transcriptional effector of a highly conserved Hippo signaling pathway, from Drosophila (Yki) to humans (YAP). In our previous Drosophila screen, we identified NELFA, a core component of the promoter-proximal pausing (PPP) complex, as a suppressor of Yki-driven hyperproliferation. Building on this observation, we investigated whether this PPP–YAP regulatory interaction is conserved in mammalian cells, using breast cancer as a model system. Using HEK293T and MDA-MB-231 cells, we demonstrate that NELFA depletion selectively amplifies YAP-driven transcription, thereby enhancing the expression of canonical YAP target genes. Whole-transcriptome analysis of NELFA-depleted MDA-MB-231 cells revealed widespread reprogramming upon NELFA loss, with strong enrichment of conserved YAP signatures, EMT and TGF-β pathways, and AP-1/TEAD-SMAD3 transcriptional networks—indicating that NELFA regulates a broad YAP-centered oncogenic module. Clinical analysis of an Indian breast cancer cohort and TCGA revealed a striking context-dependent role for NELFA. Low NELFA expression predicted poor disease-free survival in YAP-high tumors—particularly in triple-negative breast cancer (TNBC)—suggesting a tumor-suppressive role. While High NELFA expression correlated with poorer overall survival. Collectively, these findings reveal that NELFA’s role in YAP-driven transcription is context-dependent in the breast cancer setting.

ORGANISM(S): Homo sapiens

PROVIDER: GSE311396 | GEO | 2026/05/15

REPOSITORIES: GEO

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Project description:Uncontrolled Transforming growth factor-beta (TGFβ) signaling promotes aggressive metastatic properties in late-stage breast cancers. However, how TGFβ-mediated cues are directed to induce late-stage tumorigenic events is poorly understood, particularly given that TGFβ has clear tumor suppressing activity in other contexts. Here we demonstrate that the transcriptional regulators TAZ and YAP (TAZ/YAP), key effectors of the Hippo pathway, are necessary to promote and maintain TGFβ-induced tumorigenic phenotypes in breast cancer cells. Interactions between TAZ/YAP, TGFβ-activated SMAD2/3, and TEAD transcription factors reveal convergent roles for these factors in the nucleus. Genome-wide expression analyses indicate that TAZ/YAP, TEADs and TGFβ-induced signals coordinate a specific pro-tumorigenic transcriptional program. Importantly, genes cooperatively regulated by TAZ/YAP, TEAD, and TGFβ, such as the novel targets NEGR1 and UCA1, are necessary for maintaining tumorigenic activity in metastatic breast cancer cells. Nuclear TAZ/YAP also cooperate with TGFβ signaling to promote phenotypic and transcriptional changes in non-tumorigenic cells to overcome TGFβ repressive effects. Our work thus identifies crosstalk between nuclear TAZ/YAP and TGFβ signaling in breast cancer cells, revealing novel insight into late-stage disease-driving mechanisms. Expression profiling was conducted following the repression of the transcriptional regulators TAZ and YAP (TAZ/YAP), the TEAD family of transcription factors (TEAD1/2/3/4), or the TGFb signaling pathway (with SB-431542, an inhibitor of the TBRI recpeptor) in human MDA-MB-231-LM2 breast cancer cells treated with TGFβ1. Human MDA-MB-231-LM2-4 breast cancer cells were transfected with control siRNA, or siRNAs targeting TAZ/YAP or all four TEADs and were treated 24 hours later with 500pM TGFβ1 or 5mM SB-431542 for an additional 24 hours. Total RNA was isolated and twelve microarrays in total were performed, with each condition carried out three times on separate days. The Boston University Microarray Core generated the data using the Affymetrix Human Gene 1.0 St Array.

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NELFA-mediated promoter-proximal pausing restrains YAP-driven transcription and shapes context-dependent outcomes in breast cancer

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