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bioRxiv · 10.64898/2025.12.29.696819

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

Vasave, B.·Atreya, A.·Kulkarni, R.·Nagarkar, S.·Salvi, K.·Koppiker, C.·Shashidhara, L. S.·Kulkarni, M.
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Abstract

Overexpression of YAP is associated with tumor progression in multiple malignancies. YAP is the key transcriptional effector of Hippo signaling: a conserved pathway from Drosophila (Yki) to humans (YAP). In a Drosophila screen, we identified NELFA, a core component of the promoter-proximal pausing (PPP) complex, as a suppressor of Yki-driven hyperproliferation. We investigated whether PPP-YAP regulatory interaction is conserved in mammalian system. In HEK293T and MDA-MB-231 cells, we demonstrate that NELFA depletion amplifies YAP-driven transcription. Whole-transcriptome analysis of MDA-MB-231 cells revealed widespread reprogramming upon NELFA loss, with strong enrichment of YAP signatures, EMT and TGF-{beta} transcriptional networks--indicating that NELFA regulates a broad YAP-centered gene regulatory module. Clinical analysis of two independent breast cancer cohorts revealed a 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 in all the subtypes. These findings confirm that NELFAs role in YAP-driven transcription is conserved in mammalian system and it manifests in a context-dependent manner in the breast cancer.

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Vasave, B., Atreya, A., Kulkarni, R., Nagarkar, S., Salvi, K., Koppiker, C., Shashidhara, L. S., Kulkarni, M.. 2025-12-29. NELFA-mediated promoter-proximal pausing restrains YAP-driven transcription and shapes context-dependent outcomes in breast cancer. https://doi.org/10.64898/2025.12.29.696819

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