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JMJD6 Rewires ATF4-Dependent Glutathione Metabolism to Confer Ferroptosis Resistance in SPOP-Mutated Prostate Cancer
Chuanjie Zhang1,2, Jiawei Ding1, Kiat Shenq Lim1
1Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Abstract:
Ferroptosis inducers have shown therapeutic potential in prostate cancer, but tumor heterogeneity poses a barrier to their efficacy. Distinguishing the regulators orchestrating metabolic cross-talk between cancer cells could shed light on therapeutic strategies to more robustly activate ferroptosis. In this study, we found that aberrant accumulation of Jumonji domain-containing 6 (JMJD6) proteins correlated with poorer prognosis of patients with prostate cancer. Mechanistically, prostate cancer-associated speckle-type BTB/POZ protein (SPOP) mutants impaired the proteasomal degradation of JMJD6 proteins. Elevated JMJD6 and ATF4 coordinated enhancer-promoter loop interactions to stimulate the glutathione biosynthesis pathway. Independent of androgen receptor, JMJD6 recruited mediator subunits (Med1/14) to assemble de novo enhancers mapping to pivotal genes associated with glutathione metabolism, including SLC7A11, GCLM, ME1, and others. SPOP mutations thus induced intrinsic resistance to ferroptosis, dependent on enhanced JMJD6-ATF4 activity. Consequently, targeting JMJD6 rendered SPOP-mutated prostate cancer selectively sensitive to ferroptosis. The JMJD6 antagonist SKLB325 synergized with erastin in multiple preclinical prostate cancer models. Together, this study identifies JMJD6 as a druggable vulnerability in SPOP-mutated prostate cancer to increase sensitivity to ferroptosis inducers. Significance: Elevated JMJD6 induced by mutant SPOP alters the epigenetic landscape to increase glutathione biosynthesis and protect prostate cancer cells from ferroptosis, highlighting the therapeutic potential of combining JMJD6 inhibitors and ferroptosis inducers.
Insights
Aberrant accumulation of Jumonji domain-containing 6 (JMJD6) proteins, driven by SPOP mutations, promotes ferroptosis resistance in prostate cancer. Targeting JMJD6 enhances sensitivity to ferroptosis inducers, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metabolism
Background:
- Ferroptosis inducers show promise for prostate cancer, but tumor heterogeneity limits efficacy.
- Understanding metabolic cross-talk regulators is crucial for enhancing ferroptosis activation.
- Aberrant Jumonji domain-containing 6 (JMJD6) protein accumulation correlates with poor prostate cancer prognosis.
Purpose of the Study:
- To investigate the role of JMJD6 in regulating metabolic pathways and ferroptosis resistance in prostate cancer.
- To elucidate the mechanism by which SPOP mutations influence JMJD6 levels and function.
- To evaluate JMJD6 as a therapeutic target for overcoming ferroptosis resistance in SPOP-mutated prostate cancer.
Main Methods:
- Assessed JMJD6 protein levels and their correlation with patient prognosis.
- Investigated the interaction between SPOP mutants and JMJD6 degradation pathways.
- Analyzed JMJD6-mediated epigenetic regulation of glutathione biosynthesis genes.
- Evaluated the efficacy of targeting JMJD6 in combination with ferroptosis inducers in preclinical models.
Main Results:
- Prostate cancer-associated SPOP mutants impair proteasomal degradation of JMJD6.
- Elevated JMJD6 and ATF4 promote glutathione biosynthesis via enhancer-promoter interactions.
- JMJD6 recruits mediator subunits to activate genes involved in glutathione metabolism (e.g., SLC7A11, GCLM).
- SPOP mutations confer ferroptosis resistance through enhanced JMJD6-ATF4 activity.
- Targeting JMJD6 with SKLB325 synergizes with erastin, increasing ferroptosis sensitivity in SPOP-mutated prostate cancer models.
Conclusions:
- Elevated JMJD6, induced by mutant SPOP, drives epigenetic changes that increase glutathione biosynthesis and confer ferroptosis resistance.
- JMJD6 represents a druggable target in SPOP-mutated prostate cancer.
- Combining JMJD6 inhibitors with ferroptosis inducers offers a promising therapeutic strategy for prostate cancer.
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