ACSS3 promotes the tumorigenesis of non-small cell lung cancer via suppressing p53-mediated ferroptosis

Abstract

Abstract Purpose Non-small cell lung cancer (NSCLC) is a subtype of the most frequently diagnosed cancer, causing a considerable number of deaths globally. Mitochondrial dysfunction has been observed to promote malignant progression. However, the underlying mechanism is still unclear. Acyl-CoA synthetase short chain family member 3 (ACSS3) is mainly located in mitochondria, which abnormal regulation is usually accompanied by the occurrence and development of tumors. This study aimed to evaluate the potential role of ACSS3 in the tumorigenesis of NSCLC. Methods The impact of ACSS1 and ACSS3 expression levels on the survival rates of NSCLC patients was examined by online database. ACSS3 protein expression in 79 NSCLC samples and 79 adjacent tissues was evaluated by immunohistochemistry (IHC). The effect of ACSS3 on proliferation, migration and invasion of NSCLC and the molecular mechanism were investigated through in vitro experiments and xenograft tumor. Results ACSS3 expression level was correlated with the poor prognosis of NSCLC patients. ACSS3 knockdown led to mitochondrial contraction, increased ROS levels, decreased mitochondrial membrane potential, and subsequently inhibited growth of NSCLC cells in vitro and in vivo, while ACSS3 overexpression promoted these processes. Mechanistically, ACSS3 deficiency promoted ferroptosis through transcriptional control of SLC7A11 and GPX4. Further investigations found that loss of ACSS3 inhibited the SLC7A11/GPX4 axis by enhancing the stability of p53. Conclusion ACSS3 promotes NSCLC tumorigenesis through inhibiting the p53-mediated ferroptosis. As such, ACSS3 should be considered a new potential therapeutic target for the treatment of NSCLC.