JMJD6-orchestrated enhancer-hijacking strengthens ATF4-dependent glutathione metabolism to confer ferroptosis resistance in SPOP-mutated prostate cancer

Although the therapeutic potential of ferroptosis inducers in prostate cancer (PCa) was well explored, tumor heterogeneity poses barriers to precision medicine. Here we found that aberrantly accumulated jumonji domain containing 6 (JMJD6) proteins correlated with poorer prognosis of patients. Elevated JMJD6 proteins and ATF4 coordinated enhancer-promoter interaction to stimulate the glutathione biosynthesis pathway. Independent of AR or BRD4, JMJD6 recruited Mediator Subunit 1 (Med1) to assemble de novo super-enhancers mapping to pivotal genes associated with glutathione metabolism, including SLC7A11, GCLM, ME1, and others. SPOP mutations thus caused PCa intrinsic resistance to ferroptosis dependent on JMJD6/ATF4. Consequently, targeting JMJD6 rendered SPOP-mutated PCa selectively sensitive to ferroptosis. The synergistic efficacy of JMJD6 antagonist SKLB325 and erastin was robustly demonstrated in multiple pre-clinical PCa models. Together, our study identifies JMJD6 as a targetable anti-ferroptosis vulnerability in SPOP-mutated PCa.