Glutamyl-tRNA synthetase 2 regulates mitochondrial biogenesis and reactive oxygen species homeostasis mediatingenzalutamide resistance by targeting striatin 4 in prostate cancer cells.

Although enzalutamide (ENZA) has improved the overall survival of patients with metastatic prostate cancer, ENZA resistance (ENZA-resistant) inevitably develops, largely limiting its efficacy. Alternative oncogenic pathways may bypass androgen receptor (AR) signaling to promote ENZA-resistant. Glutamyl-tRNA synthetase 2 (EARS2) is involved in mitochondrial biogenesis and is associated with cancer, but its action mechanism in prostate cancer (PCa) is not well defined. EARS2 expression was detected in primary PCa and castrate-resistant prostate cancer samples, ENZA-resistant cell lines, and ENZA-resistant xenograft models, and the prognostic relationship of EARS2 in patients with PCa was analyzed. In AR-sensitive LNCaP cells, changes in EARS2 expression were explored before and after stimulation with dihydrotestosterone (DHT) or bicalutamide. AR was knocked down in AR-positive LNCaP and C4-2B cells to explore the relationship between EARS2 and AR. The effect of EARS2 on PCa cells was further explored. ENZA-resistant xenograft model was built to explore the effect of EARS2 on tumorigenesis in vivo. EARS2 was knocked down in C4-2B-ENZA-resistant, and the relationship between EARS2 and mitochondrial biogenesis and reactive oxygen species (ROS) homeostasis was investigated in PCa cells. Finally, the relationship between EARS2 and striatin 4 (STRN4) was explored. EARS2 expression was elevated in PCa and correlated with ENZA-resistant, and high EARS2 expression was associated with poorer patient prognosis. In androgen-sensitive LNCaP cells, DHT inhibited EARS2 expression, and silencing AR increased EARS2 expression. Suppressing EARS2 inhibited the proliferation, colony formation, migration and invasion ability, down-regulated the IC50 of ENZA in ENZA-resistant cells, and promoted apoptosis. Stable EARS2 downregulation in C4-2B-ENZA-resistant significantly inhibited tumor growth. Suppressing EARS2 in ENZA-resistant cells may lead to increased mitochondrial biogenesis and ROS generation. Mechanistically, EARS2 inhibited mitochondrial biogenesis and ROS generation in PCa cells by targeting STRN4. EARS2 targets STRN4 to modulate mitochondrial biogenesis and ROS homeostasis mediating ENZA-resistant.