KDM6A loss enhances oxidative phosphorylation uncovering tissue-level convergent evolution
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.
Authors
- Valentina Giansanti (ORCID: https://orcid.org/0000-0003-0617-6245)
- Alessandra Boletta (ORCID: https://orcid.org/0000-0002-4704-4006)
- Richard L. Bennett (ORCID: https://orcid.org/0000-0002-0243-2443)
- Laura Cassina (ORCID: https://orcid.org/0000-0002-7350-3069)
- Dalia Rosano (ORCID: https://orcid.org/0000-0002-7372-9535)
- Davide Cittaro (ORCID: https://orcid.org/0000-0003-0384-3700)
- Annarita Miluzio (ORCID: https://orcid.org/0000-0002-2838-2659)
- Camilla Ferrari (ORCID: https://orcid.org/0000-0002-9019-259X)
- Veronica Ruggieri (ORCID: https://orcid.org/0009-0009-2243-3804)
- Michele Ciboddo (ORCID: https://orcid.org/0000-0002-5175-5185)
- Giovanni Tonon (ORCID: https://orcid.org/0000-0003-2973-5038)
- Chiara D’Ercole (ORCID: https://orcid.org/0000-0003-0077-9870)
- Maurizio Fanciulli (ORCID: https://orcid.org/0000-0002-5281-4191)
- Luca Madaro (ORCID: https://orcid.org/0000-0003-0839-5724)
- Tiziana Bruno (ORCID: https://orcid.org/0000-0003-0352-4523)
- José Manuel García-Manteiga (ORCID: https://orcid.org/0000-0002-5481-040X)
- Federica Corigliano (ORCID: https://orcid.org/0000-0003-4331-8353)
- Stefano Biffo (ORCID: https://orcid.org/0000-0002-3780-1050)
- Telmo Pievani
- Antonino Alex Cartalemi (ORCID: https://orcid.org/0000-0003-1523-4443)
- ILARIA VILLANTI
- Jonathan Licht
- Simona Punzi
- Guido Gatti
- Daphné Dupéré-Richer
- Gemma Crupi
Institutions
- University of Rome Tor Vergata (IT)
- Van Andel Institute (US)
- University of Padua (IT)
- Vita-Salute San Raffaele University (IT)
- University of Milan (IT)
- National Cancer Institute (MY)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- Istituto Nazionale Genetica Molecolare (IT)
- Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele (IT)
- National Cancer Research Institute (GB)
- Sapienza University of Rome (IT)
Publication Details
- Journal
- The EMBO Journal
- Published
- 2026-09-04
- DOI
- https://doi.org/10.1038/s44318-026-00891-0
- Primary Topic
- Cancer, Hypoxia, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Center for Cancer Research
- Fondazione AIRC per la ricerca sul cancro ETS
- Multiple Myeloma Research Foundation
- Leukemia and Lymphoma Society
- Fondazione Cariplo
- Associazione Italiana per la Ricerca sul Cancro
- National Institutes of Health