Authors
Antonino Alex Cartalemi, Dalia Rosano, Camilla Ferrari, Gemma Crupi, Laura Cassina, Guido Gatti, Federica Corigliano, Simona Punzi, Ilaria Villanti, Daphné Dupéré-Richer, Chiara D'Ercole, Veronica Ruggieri, Annarita Miluzio, Tiziana Bruno, Jose Manuel Garcia Manteiga, Valentina Giansanti, Richard L Bennett, Davide Cittaro, Luca Madaro, Alessandra Boletta, Telmo Pievani, Stefano Biffo, Maurizio Fanciulli, Michele Ciboddo, Jonathan Licht, Giovanni Tonon
Published in
The EMBO journal. Sep 04, 2026. Epub Sep 04, 2026.
Abstract
The tumor suppressor KDM6A/UTX, a histone demethylase and a 2-oxoglutarate-dependent dioxygenase, is frequently lost in many cancer types. We show that KDM6A loss pervasively activates oxidative phosphorylation in several solid tumors, generating a pseudo-hyperoxic environment, opposite from the pseudo-hypoxia observed in VHL-mutated renal carcinomas. Mechanistically, KDM6A sustains the expression of the coil-coil domain gene CCDC3, which inhibits CREB1-driven transcription of the mitochondrial regulator PPARGC1A. In the hematological cancer multiple myeloma where KDM6A is frequently deleted, its loss similarly promotes oxidative phosphorylation, but via an alternative mechanism: the increased transfer of mitochondria from stromal to myeloma cells via tunneling nanotubes, triggered by the loss of the mTORC1 inhibitor TRAF3IP3. Beyond cancer, KDM6A regulates oxidative phosphorylation also during development and in adult tissues, engaging either the CCDC3-CREB1 or the TRAF3IP3-mTORC1 pathways. These mutually exclusive associations suggest a tissue-level convergent evolution, positioning KDM6A as a central modulator of mitochondrial activity through context-specific partners.
PMID:
42697963
Bibliographic data and abstract were imported from PubMed on 05 Sep 2026.
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