KDM6A loss enhances oxidative phosphorylation uncovering tissue-level convergent evolution

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. Loss of the oxygen-sensing chromatin regulator KDM6A/UTX is frequent in cancer cells. Here, this is shown to promote a pseudo-hyperoxic metabolic state through alternative tissue-specific pathways for controlling oxidative phosphorylation, highlighting tissue-level convergent evolution as a mechanism of metabolic regulation. Loss of KDM6A activates oxidative phosphorylation (OXPHOS) across multiple solid tumor types and increases mitochondrial mass. In solid tumors, KDM6A restrains OXPHOS through a CCDC3-CREB1-PPARGC1A pathway controlling mitochondrial biogenesis. In multiple myeloma, KDM6A loss activates mTORC1 through TRAF3IP3 repression and promotes mitochondrial transfer from stromal cells via tunneling nanotubes. KDM6A-dependent regulation of OXPHOS also operates in normal tissues and during development. Loss of KDM6A activates oxidative phosphorylation (OXPHOS) across multiple solid tumor types and increases mitochondrial mass. In solid tumors, KDM6A restrains OXPHOS through a CCDC3-CREB1-PPARGC1A pathway controlling mitochondrial biogenesis. In multiple myeloma, KDM6A loss activates mTORC1 through TRAF3IP3 repression and promotes mitochondrial transfer from stromal cells via tunneling nanotubes. KDM6A-dependent regulation of OXPHOS also operates in normal tissues and during development. Loss of the oxygen-sensing chromatin regulator KDM6A drives a pseudo-hyperoxic metabolic state through two pathways, one based on increased mitochondria synthesis, and another via increased mitochondria trafficking from stromal cells to cancer cells.