Hijacking the expression of KDM4B-dependent metabolic genes potentiates curcumin antitumor effects

Abstract Cancer therapies often cause significant side effects, driving the search for more tolerable and effective treatments. Natural products, such as the polyphenol curcumin, exhibit promising anticancer properties by modulating cell death pathways. We demonstrated that curcumin inhibits growth and migration of adrenocortical cancer (ACC) cells, a rare tumor with no available targeted therapy. In these cells curcumin caused a shift in cell metabolism toward a glycolytic phenotype and an increased glutamine/glutamate dependency. However, why cells adapt their metabolism promoting glutamate synthesis remains unclear. Curcumin acts as a pro-oxidant in ACC cells, elevating reactive oxygen species (ROS) and, consequently, cells adopt a defense mechanism increasing glutathione, a glutamate-containing antioxidant, and lipid droplet (LD) content, preventing oxidative stress. Key genes in this metabolic adaptation are SLC1A5, SLC27A2, ELOVL5, whose expression is positively regulated by curcumin and abrogated by the ROS scavenger N-acetyl-cysteine (NAC). Mechanistically, we evidenced that curcumin-induced ROS increase transcription factor HIF1α, which drives the upregulation of nuclear receptor PPARγ and the Jumonji histone demethylases (KDMs) family member KDM4B, affecting ACC cell metabolism and epigenome. The use of a KDM4B inhibitor potentiated curcumin anti-proliferative effects in vitro and, more importantly, on ex vivo cultures of H295R xenografts tissue grown in a 3D bioreactor. Collectively these data prove ACC cells’ ability to change their metabolism to counteract curcumin-induced oxidative stress through epigenetic modifications. The identification of KDM4B as the master regulator behind the changes provides novel insights into combinatorial strategies for improving ACC patients’ outcome.