Nuclear Translocation of LDHA Promotes the Catabolism of BCAAs to Sustain GBM Cell Proliferation through the TxN Antioxidant Pathway
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 epigen...
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MDPI AG
2023-05-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/11/9365 |
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| author | Zhujun Li Zhiyan Gu Lan Wang Yun Guan Yingying Lyu Jialong Zhang Yin Wang Xin Wang Ji Xiong Ying Liu |
| author_facet | Zhujun Li Zhiyan Gu Lan Wang Yun Guan Yingying Lyu Jialong Zhang Yin Wang Xin Wang Ji Xiong Ying Liu |
| author_sort | Zhujun Li |
| collection | DOAJ |
| description | 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 <i>IDH</i> mutant gliomas. However, glioblastomas (GBMs) express wild type <i>IDH</i>. 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 progression of GBMs. |
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| last_indexed | 2024-03-11T03:06:08Z |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-eced3638e30b484d910d4142dc2a81d92023-11-18T07:58:01ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-05-012411936510.3390/ijms24119365Nuclear Translocation of LDHA Promotes the Catabolism of BCAAs to Sustain GBM Cell Proliferation through the TxN Antioxidant PathwayZhujun Li0Zhiyan Gu1Lan Wang2Yun Guan3Yingying Lyu4Jialong Zhang5Yin Wang6Xin Wang7Ji Xiong8Ying Liu9Department of Pathology, School of Basic Medical Sciences, Fudan University, Yixueyuan Rd. 138, Shanghai 200032, ChinaDepartment of Pathology, School of Basic Medical Sciences, Fudan University, Yixueyuan Rd. 138, Shanghai 200032, ChinaDepartment of Pathology, School of Basic Medical Sciences, Fudan University, Yixueyuan Rd. 138, Shanghai 200032, ChinaCyberknife Center, Department of Neurosurgery, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai 200040, ChinaDepartment of Neurosurgery, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai 200040, ChinaDepartment of Pathology, School of Basic Medical Sciences, Fudan University, Yixueyuan Rd. 138, Shanghai 200032, ChinaDepartment of Pathology, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai 200040, ChinaCyberknife Center, Department of Neurosurgery, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai 200040, ChinaDepartment of Pathology, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai 200040, ChinaDepartment of Pathology, School of Basic Medical Sciences, Fudan University, Yixueyuan Rd. 138, Shanghai 200032, ChinaGlutamate 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 <i>IDH</i> mutant gliomas. However, glioblastomas (GBMs) express wild type <i>IDH</i>. 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 progression of GBMs.https://www.mdpi.com/1422-0067/24/11/9365lactate dehydrogenase Aglutamatebranched-chain amino acid transaminase 1redox balancethioredoxinGBM |
| spellingShingle | Zhujun Li Zhiyan Gu Lan Wang Yun Guan Yingying Lyu Jialong Zhang Yin Wang Xin Wang Ji Xiong Ying Liu Nuclear Translocation of LDHA Promotes the Catabolism of BCAAs to Sustain GBM Cell Proliferation through the TxN Antioxidant Pathway International Journal of Molecular Sciences lactate dehydrogenase A glutamate branched-chain amino acid transaminase 1 redox balance thioredoxin GBM |
| title | Nuclear Translocation of LDHA Promotes the Catabolism of BCAAs to Sustain GBM Cell Proliferation through the TxN Antioxidant Pathway |
| title_full | Nuclear Translocation of LDHA Promotes the Catabolism of BCAAs to Sustain GBM Cell Proliferation through the TxN Antioxidant Pathway |
| title_fullStr | Nuclear Translocation of LDHA Promotes the Catabolism of BCAAs to Sustain GBM Cell Proliferation through the TxN Antioxidant Pathway |
| title_full_unstemmed | Nuclear Translocation of LDHA Promotes the Catabolism of BCAAs to Sustain GBM Cell Proliferation through the TxN Antioxidant Pathway |
| title_short | Nuclear Translocation of LDHA Promotes the Catabolism of BCAAs to Sustain GBM Cell Proliferation through the TxN Antioxidant Pathway |
| title_sort | nuclear translocation of ldha promotes the catabolism of bcaas to sustain gbm cell proliferation through the txn antioxidant pathway |
| topic | lactate dehydrogenase A glutamate branched-chain amino acid transaminase 1 redox balance thioredoxin GBM |
| url | https://www.mdpi.com/1422-0067/24/11/9365 |
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