Abstract 433: BCAT1 promotes HCC metabolic reprogramming and survival through HIF-1α stabilization

Abstract

Abstract Hepatocellular carcinoma (HCC) is a highly lethal primary liver malignancy characterized by hypoxia, a common feature of solid tumors, particularly in HCC. Hypoxia-inducible factors (HIFs) play a pivotal role in mediating various cellular processes, such as metabolic adaptation, to support the survival of hypoxic cells. The cytosolic form of branched-chain amino transferase (BCAT1) is responsible for the reversible transamination reaction between branched-chain keto-amino acids (BCKAs) and branched-chain amino acids (BCAAs), facilitating the interconversion between α-ketoglutarate (α-KG) and glutamate. Interestingly, we found that in the context of HCC, BCAT1 consumes α-KG, thereby favoring the stabilization of HIF-1α through suppressing the α-KG-dependent prolyl hydroxylase (PHD). Knockdown (KD) or knockout (KO) of BCAT or BCAT inhibitor (ERG245) suppressed HIF-1 stability, as well as HIF-1 dependent transcriptomic and metabolic changes. Mass spectrometry (MS)-based isotopic carbon tracing showed that KD/KO or ERG 245 suppressed hypoxia/HIF-1-induced glycolytic flux. Interestingly, ERG245 effectively inhibited the proliferative output of hypoxic HCC cells and suppressed HCC growth. ERG245 also profoundly inhibited HCC growth in vitro and in vivo together with Sorafenib, a tyrosine kinase inhibitor (TKI) used in HCC by increasing the apoptotic cell death. Furthermore, we confirmed that the expressions of BCAT1 and the HIF-1α-targeted metabolic genes are positively correlated in human HCCs. Our findings unequivocally demonstrate that BCAT1 confers a growth advantage to HCC cells by stabilizing HIF-1α and orchestrating HIF-1α-mediated metabolic reprogramming. Consequently, targeting BCAT1 emerges as a promising therapeutic strategy for HCC patients. Funding Support: This work was supported by the Centre for Oncology and Immunology under the Health@InnoHK initiative funded by the Innovation and Technology Commission, The Government of Hong Kong SAR, China and National Natural Science Foundation of China (NSFC) (82173123, C.C.-L.W.) Citation Format: Misty Shuo Zhang, Kenneth Kin-Leung Kwan, Weixing Li, Adonia E. Papathanassiu, Irene Oi-Lin Ng, Carmen Chak-Lui Wong. BCAT1 promotes HCC metabolic reprogramming and survival through HIF-1α stabilization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 433.