Emerging hypoxia-driven mechanisms rewiring metabolism and gene regulation in prostate cancer
- Autores: Maider Fagoaga Eugui
- Directores de la Tesis: Arkaitz Carracedo Pérez (dir. tes.), Miren Edurne Berra Ramírez (codir. tes.)
- Lectura: En la Universidad del País Vasco - Euskal Herriko Unibertsitatea ( España ) en 2025
- Idioma: inglés
- Tribunal Calificador de la Tesis: Lorea Valcárcel Jiménez (secret.)
- Programa de doctorado: Programa de Doctorado en Biología Molecular y Biomedicina / Molecular Biology and Biomedicine por la Universidad del País Vasco/Euskal Herriko Unibertsitatea
- Menciones:
- Internacional
- Calificación: Sobresaliente Cum Laude
- Enlaces
- Tesis en acceso abierto en: ADDI
- Resumen
Hypoxia is a major driver of metabolic adaptation in cancer, yet many aspects of how cells sense and respond to changes in oxygen availability remain unresolved. This thesis explores both canonical and emerging hypoxic regulatory mechanisms in prostate cancer (PCa) and beyond. First, we identify PGC1α as a key modulator of the hypoxic response in PCa. Through its interaction with ERRα, PGC1α transcriptionally induces EGLN1/PHD2, promoting oxygen-dependent HIFα degradation and restraining hypoxic signaling. Loss of PGC1α, and consequent disruption of the PGC1α-EGLN1-HIF axis, impairs oxygen sensing, promotes pseudohypoxia and enhances tumor progression. Second, our data uncover a widespread, chronic hypoxia-driven repression of the polyamine (PA) biosynthesis pathway, which contributes to a profound remodeling of alternative splicing. This reveals both PA-dependent and independent contributions of hypoxia to RNA processing. Finally, we characterize a previously unrecognized acute hypoxic response that is not exclusive to PCa, in which oxygen scarcity promptly triggers lysosomal exocytosis and PA secretion via a yet unidentified sensing mechanism. Together, these findings advance our understanding of oxygen sensing and its relationship with metabolism, gene regulation, and extracellular remodeling.
