Abstract
Prostate cancer (PCa) is the most prevalent malignancy among men worldwide. Advanced prostate cancer is characterized by aggressive progression, limited therapeutic response, and poor prognosis. Elucidating its oncogenic mechanisms may provide new opportunities for targeted intervention. Increasing evidence suggests that modulating cytoprotective autophagy represents a promising strategy for improving cancer treatment efficacy and overcoming drug resistance. Here, we identified the G protein subunit GNG4 as a crucial regulator of prostate cancer development. GNG4 expression was markedly elevated in advanced prostate cancer phenotypes and positively correlated with tumor survival, apoptosis, and migration. Further analysis demonstrated that GNG4 depletion suppressed autophagy and enhanced cellular sensitivity to enzalutamide. Mechanistically, GNG4 interacts with GNB1 to stabilize the downstream effector protein GNAI3 through the ubiquitination-proteasome pathway. These three distinct G protein subunits form a functional complex that regulates intracellular autophagy and subsequently influences the malignant behavior of prostate cancer. Furthermore, inhibition of autophagy or GNG4 knockdown significantly increased the antitumor efficacy of enzalutamide both in vitro and in vivo. Our findings identified GNG4 as a pivotal modulator of prostate cancer progression and proposed it as a promising therapeutic target to enhance the clinical response to enzalutamide. GNG4 interacts with GNB1 to stabilize GNAI3 via the ubiquitination-proteasome pathway, thereby activating autophagy. This process promotes prostate cancer progression and resistance to androgen receptor signaling inhibitors (ARSis). In contrast, GNG4 knockdown or pharmacological inhibition of autophagy restores ARSI sensitivity and suppresses tumor growth.