Nuclear Translocation of LDHA Promotes the Catabolism of BCAAs to Sustain GBM Cell Proliferation through the TxN Antioxidant Pathway

作者：Zhujun Li, Zhiyan Gu, Lan Wang, Yun Guan, Yingying Lyu, Jialong Zhang, Yin Wang, Xin Wang, Ji Xiong, Ying Liu · 发表于：International Journal of Molecular Sciences · 年份：2023 · DOI：10.3390/ijms24119365 · 被引用次数：19 · 研究领域：Glioma Diagnosis and Treatment、Epigenetics and DNA Methylation、Cancer, Hypoxia, and Metabolism

Glutamate is excitotoxic to neurons. The entry of glutamine or glutamate from the blood into the brain is limited. To overcome this, branched-chain amino acids (BCAAs) catabolism replenishes the glutamate in brain cells. Branched-chain amino acid transaminase 1 (BCAT1) activity is silenced by epigenetic methylation in IDH mutant gliomas. However, glioblastomas (GBMs) express wild type IDH. Here, we investigated how oxidative stress promotes BCAAs’ metabolism to maintain intracellular redox balance and, consequently, the rapid progression of GBMs. We found that reactive oxygen species (ROS) accumulation promoted the nuclear translocation of lactate dehydrogenase A (LDHA), which triggered DOT1L (disruptor of telomeric silencing 1-like)-mediated histone H3K79 hypermethylation and enhanced BCAA catabolism in GBM cells. Glutamate derived from BCAAs catabolism participates in antioxidant thioredoxin (TxN) production. The inhibition of BCAT1 decreased the tumorigenicity of GBM cells in orthotopically transplanted nude mice, and prolonged their survival time. In GBM samples, BCAT1 expression was negatively correlated with the overall survival time (OS) of patients. These findings highlight the role of the non-canonical enzyme activity of LDHA on BCAT1 expression, which links the two major metabolic pathways in GBMs. Glutamate produced by the catabolism of BCAAs was involved in complementary antioxidant TxN synthesis to balance the redox state in tumor cells and promote the progressio...