GSTA1 deficiency drives neuroendocrine differentiation via TNFRSF13B/c-FOS/CHGA axis in prostate cancer.

Androgen deprivation therapy (ADT) is the cornerstone of prostate cancer (PCa) treatment. Prolonged ADT inevitably increases the risk of neuroendocrine differentiation, which leads to the development of hormone-refractory subtypes. In this study, we explored the molecular mechanisms underlying the neuroendocrine differentiation of PCa cells under ADT. We performed digital spatial profiling (DSP) sequencing using tissue microarrays from five patients with PCa who underwent neoadjuvant therapy before radical prostatectomy at the Nanjing Drum Tower Hospital. Glutathione S-transferase alpha 1 (GSTA1) was identified as a driver of neuroendocrine differentiation in PCa cells using DSP sequencing of tissue microarrays prepared from clinical samples. Following enzalutamide (ENZ) treatment, GSTA1 expression is inhibited. Decreased GSTA1 levels have also been reported in patients with neuroendocrine PCa (NEPC). GSTA1 knockdown leads to increased intracellular reactive oxygen species (ROS), which can activate the inflammatory gene, tumor necrosis factor receptor superfamily member 13B (TNFRSF13B). TNFRSF13B induces c-Fos expression, forming a transcriptional complex with c-Jun, thereby regulating chromogranin A (CHGA) and promoting the neuroendocrine phenotype. Our study suggested that GSTA1 deficiency leads to elevated ROS levels and activation of TNFRSF13B and c-FOS, which subsequently transcriptionally regulate CHGA and ultimately drive neuroendocrine differentiation in PCa.