Loss of ZFHX3, a tumor suppressor in prostate cancer, enhances oxidative phosphorylation via Complex II assembly to promote cell proliferation

Metabolic reprogramming is a hallmark of human cancers, including prostate cancer (PCa), yet its genomic drivers remain poorly understood. Unlike most cancers, which exhibit the Warburg effect, PCa usually possesses elevated oxidative phosphorylation (OXPHOS). This study investigates whether and how the loss of ZFHX3, a tumor suppressor frequently inactivated in advanced PCa, modulates cellular metabolism. Whereas ZFHX3 deep deletion in human PCa correlated with much worse patient overall survival than somatic mutations, it also correlated with enriched mitochondrial pathways. Analyses of ZFHX3-knockout PCa cells demonstrated a bioenergetic shift toward higher OXPHOS, characterized by enlarged mitochondria, increased tricarboxylic acid (TCA) cycle activity, enhanced ATP production, reduced reactive oxygen species, and improved redox homeostasis. Mechanistically, ZFHX3 loss elevated protein levels of Complex II subunits and their assembly without increasing their gene transcription. Functionally, inhibiting mitochondrial respiration or the SDHB subunit of Complex II abolished the ZFHX3-loss-enhanced cell proliferation, whereas inhibiting Complex II enzymatic activity did not. These findings uncover a novel ZFHX3 function in maintaining mitochondrial metabolic homeostasis, establish its loss as a driver of the OXPHOS shift during PCa progression, and highlight the ZFHX3 loss-Complex II disruption as a potential therapeutic opportunity for targeting PCa with ZFHX3 loss.