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UTX (KDM6A), a histone H3K27 demethylase mutated in many cancers, is traditionally viewed as a tumor suppressor during cancer initiation. Paradoxically, wild‑type UTX persists in most common solid tumors, suggesting a tumor‑maintaining role in established cancers. In this thesis, we investigate how UTX regulates DNA damage responses and therapeutic sensitivity in non‑small cell lung cancer (NSCLC) models. We uncover a demethylase‑independent function of UTX in promoting DNA double‑strand break (DSB) repair that sustains tumor cell proliferation and survival. Mechanistically, UTX associates with PARP1 and the MLL4 (KMT2D) complex and promotes their recruitment to sites of DNA damage. Loss of UTX impairs PARP1‑dependent repair and markedly enhances tumor sensitivity to the PARP inhibitor olaparib and to cisplatin. In xenograft models, genetic UTX inactivation—but not catalytic inhibition with the H3K27 demethylase inhibitor GSK‑J4—suppresses tumor growth and augments the efficacy of olaparib and cisplatin. Together, these findings identify UTX as a critical non‑catalytic mediator of DNA repair–driven tumor maintenance and highlight UTX loss as a therapeutic vulnerability that can be exploited to potentiate DNA damage–based cancer therapies.

Taiwan International Graduate Program in Molecular Medicine, National Yang-Ming University and Academia Sinica Doctoral Dissertation