美国纪念斯隆-凯瑟琳癌症研究中心Hans-Guido Wendel研究组的一项最新工作发现，NRF2的致癌作用依赖于果糖胺-3激酶的去糖基化作用。相关论文于2019年8月9日发表于国际学术期刊《细胞》上。

课题组发现NRF2的活性依赖于果糖胺-3-激酶（FN3K），一个能够促使蛋白质去糖基化的激酶。 当FN3K不存在时，NRF2变得广泛地糖基化、不稳定并且在与小MAF蛋白结合以及转录激活时出现缺陷。此外，体内由MYC和Keap1失活引发的肝细胞癌的发展依赖于FN3K。 N-乙酰半胱氨酸处理能够部分地挽救FN3K缺失对NRF2驱动的肿瘤表型的影响，这表明NRF2介导的氧化还原平衡在其中的关键作用。质谱分析显示其他蛋白也具有FN3K敏感的糖基化，包括翻译因子、热休克蛋白和组蛋白。糖基化如何影响这些功能仍有待定义。总之，这些研究揭示了细胞蛋白糖基化出人意料的作用，并提示FN3K是癌症中NRF2活性的可靶向调节者。

据悉，转录因子NRF2调控与癌症有关的细胞应激程序，并且人们对靶向NRF2的治疗很感兴趣。

附：英文原文

Title: The Oncogenic Action of NRF2 Depends on De-glycation by Fructosamine-3-Kinase

Author: Viraj R. Sanghvi, Josef Leibold, Marco Mina, Prathibha Mohan, Marjan Berishaj, Zhuoning Li, Matthew M. Miele, Nathalie Lailler, Chunying Zhao, Elisa de Stanchina, Agnes Viale, Leila Akkari, Scott W. Lowe, Giovanni Ciriello, Ronald C. Hendrickson, Hans-Guido Wendel

Issue&Volume: Volume 178 Issue 4

Abstract: The NRF2 transcription factor controls a cell stress program that is implicated in cancer and there is great interest in targeting NRF2 for therapy. We show that NRF2 activity depends on Fructosamine-3-kinase (FN3K)—a kinase that triggers protein de-glycation. In its absence, NRF2 is extensively glycated, unstable, and defective at binding to small MAF proteins and transcriptional activation. Moreover, the development of hepatocellular carcinoma triggered by MYC and Keap1 inactivation depends on FN3K in vivo. N-acetyl cysteine treatment partially rescues the effects of FN3K loss on NRF2 driven tumor phenotypes indicating a key role for NRF2-mediated redox balance. Mass spectrometry reveals that other proteins undergo FN3K-sensitive glycation, including translation factors, heat shock proteins, and histones. How glycation affects their functions remains to be defined. In summary, our study reveals a surprising role for the glycation of cellular proteins and implicates FN3K as targetable modulator of NRF2 activity in cancer.

DOI: https://doi.org/10.1016/j.cell.2019.07.031

Source: https://www.cell.com/cell/fulltext/S0092-8674(19)30830-X