具有不同催化活性的代谢酶异柠檬酸脱氢酶1突变体可调节肿瘤模型中的表型严重程度。

Catalytically distinct metabolic enzyme isocitrate dehydrogenase 1 mutants tune phenotype severity in tumor models.

作者信息

Schwartz Ashley V, Chao Grace, Robinson Mikella, Conley Brittany M, Ahmed Adam Mowaffaq Adam, Wells Grace A, Hoang An, Albekioni Elene, Gallo Cecilia, Weeks Joi, Yunker Katelyn, Quichocho Giovanni, George Uduak Z, Niesman Ingrid, House Carrie D, Turcan Şevin, Sohl Christal D

机构信息

Computational Science Research Center, San Diego State University, San Diego, California, USA.

Department of Biology, San Diego State University, San Diego, California, USA.

出版信息

J Biol Chem. 2025 Apr 4;301(5):108477. doi: 10.1016/j.jbc.2025.108477.

DOI:10.1016/j.jbc.2025.108477

PMID:40188944

Abstract

Mutations in isocitrate dehydrogenase 1 (IDH1) impart a neomorphic reaction that produces D-2-hydroxyglutarate (D2HG), which can inhibit DNA demethylases to drive tumorigenesis. Mutations affect residue R132 and display distinct catalytic profiles for D2HG production. We show that catalytic efficiency of D2HG production is greater in IDH1 R132Q than R132H mutants, and expression of IDH1 R132Q in cellular and xenograft models leads to higher D2HG concentrations in cells, tumors, and sera compared to R132H. Though expression of IDH1 R132Q leads to hypermethylation in DNA damage pathways, DNA hypomethylation is more notable when compared to IDH1 R132H expression. Transcriptome analysis shows increased expression of many pro-tumor pathways upon expression of IDH1 R132Q versus R132H, including transcripts of EGFR and PI3K signaling pathways. Thus, IDH1 mutants appear to modulate D2HG levels via altered catalysis and are associated with distinct epigenetic and transcriptomic consequences, with higher D2HG levels appearing to be associated with more aggressive tumors.

摘要

异柠檬酸脱氢酶1（IDH1）的突变引发一种新形态反应，产生D-2-羟基戊二酸（D2HG），其可抑制DNA去甲基化酶从而驱动肿瘤发生。突变影响第132位残基，并表现出不同的D2HG产生催化特征。我们发现，与R132H突变体相比，IDH1 R132Q产生D2HG的催化效率更高，并且在细胞和异种移植模型中，与R132H相比，IDH1 R132Q的表达导致细胞、肿瘤和血清中D2HG浓度更高。尽管IDH1 R132Q的表达导致DNA损伤途径中的高甲基化，但与IDH1 R132H的表达相比，DNA低甲基化更为明显。转录组分析显示，与R132H相比，IDH1 R-132Q表达后许多促肿瘤途径的表达增加，包括表皮生长因子受体（EGFR）和磷脂酰肌醇-3-激酶（PI3K）信号通路的转录本。因此，IDH1突变体似乎通过改变催化作用来调节D2HG水平，并与不同的表观遗传和转录组结果相关，较高的D2HG水平似乎与更具侵袭性的肿瘤相关。