PDHA1–acetylation signaling suppresses cuproptosis to attenuate anti-androgen effect in prostate cancer

TL;DR

This study shows that PDHA1 acetylation suppresses a copper-dependent cell death process, reducing the effectiveness of prostate cancer treatment, and suggests targeting PDHA1 could restore treatment sensitivity.

Contribution

The paper identifies PDHA1 as a novel modulator of cuproptosis and enzalutamide resistance in prostate cancer.

Findings

PDHA1 enhances histone acetylation and SLC7A11 expression, promoting glutathione synthesis and copper chelation.

Inhibiting PDHA1 restores cuproptosis and increases enzalutamide efficacy in prostate cancer models.

Cuproptosis suppression by PDHA1 contributes to resistance against anti-androgen therapy in CRPC.

Abstract

Acquired resistance to enzalutamide (Enz) presents a significant challenge in castration-resistant prostate cancer (CRPC), and overcoming this resistance remains an unmet clinical need. Here, we identified cuproptosis, a copper-dependent mechanism of regulated cell death, as a key driver of Enz resistance. Both in vitro and in vivo models demonstrated that pyruvate dehydrogenase E1 alpha subunit (PDHA1) serves as a critical modulator of cuproptosis and Enz sensitivity. Mechanistically, PDHA1 increases intracellular acetyl-CoA, enhancing histone H3K27 acetylation and upregulating solute carrier family 7 member 11 (SLC7A11), which promotes cysteine uptake and glutathione (GSH) synthesis. Elevated GSH chelates intracellular copper, thereby suppressing cuproptosis and reducing Enz efficacy. Targeting PDHA1 significantly restores cuproptosis and sensitizes CRPC cells to Enz treatment. These findings underscore the potential of PDHA1 inhibition to counteract Enz resistance by reactivating cuproptosis, offering a promising therapeutic approach for treating refractory prostate cancer.

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