Tyrosine catabolism enhances genotoxic chemotherapy by suppressing translesion DNA synthesis in epithelial ovarian cancer.

Cell metabolism Pub Date : 2023-11-07 Epub Date: 2023-10-26 DOI:10.1016/j.cmet.2023.10.002
Jie Li, Cuimiao Zheng, Qiuwen Mai, Xi Huang, Wenfeng Pan, Jingyi Lu, Zhengfan Chen, Suman Zhang, Chunyu Zhang, Hua Huang, Yangyang Chen, Hongbo Guo, Zhenyin Wu, Chunnuan Deng, Yiting Jiang, Bo Li, Junxiu Liu, Shuzhong Yao, Chaoyun Pan
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Abstract

Amino acid metabolism has been actively investigated as a potential target for antitumor therapy, but how it may alter the response to genotoxic chemotherapy remains largely unknown. Here, we report that the depletion of fumarylacetoacetate hydrolase (FAH), an enzyme that catalyzes the final step of tyrosine catabolism, reduced chemosensitivity in epithelial ovarian cancer (EOC). The expression level of FAH correlated significantly with chemotherapy efficacy in patients with EOC. Mechanistically, under genotoxic chemotherapy, FAH is oxidized at Met308 and translocates to the nucleus, where FAH-mediated tyrosine catabolism predominantly supplies fumarate. FAH-produced fumarate binds directly to REV1, resulting in the suppression of translesion DNA synthesis (TLS) and improved chemosensitivity. Furthermore, in vivo tyrosine supplementation improves sensitivity to genotoxic chemotherapeutics and reduces the occurrence of therapy resistance. Our findings reveal a unique role for tyrosine-derived fumarate in the regulation of TLS and may be exploited to improve genotoxic chemotherapy through dietary tyrosine supplementation.

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酪氨酸分解代谢通过抑制上皮性卵巢癌症跨病变DNA合成来增强基因毒性化疗。
氨基酸代谢作为抗肿瘤治疗的潜在靶点已被积极研究,但它如何改变对基因毒性化疗的反应在很大程度上仍是未知的。在此,我们报道了富马酸乙酰乙酸水解酶(FAH)的缺失,这种酶催化酪氨酸分解代谢的最后一步,降低了上皮性卵巢癌症(EOC)的化学敏感性。在EOC患者中,FAH的表达水平与化疗疗效显著相关。从机制上讲,在基因毒性化疗下,FAH在Met308被氧化并转移到细胞核,在那里FAH介导的酪氨酸分解代谢主要提供富马酸盐。FAH产生的富马酸盐直接与REV1结合,从而抑制跨病变DNA合成(TLS)并提高化学敏感性。此外,体内补充酪氨酸提高了对基因毒性化疗药物的敏感性,并减少了治疗耐药性的发生。我们的研究结果揭示了酪氨酸衍生的富马酸盐在TLS调节中的独特作用,并可用于通过饮食补充酪氨酸来改善遗传毒性化疗。
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