2. Academic Validation
  3. Isonicotinylation is a histone mark induced by the anti-tuberculosis first-line drug isoniazid

Isonicotinylation is a histone mark induced by the anti-tuberculosis first-line drug isoniazid

  • Nat Commun. 2021 Sep 20;12(1):5548. doi: 10.1038/s41467-021-25867-y.
Yuhan Jiang 1,  Yixiao Li 1,  Cheng Liu 1,  Lei Zhang 1,  Danyu Lv 1,  Yejing Weng 2,  Zhongyi Cheng 2,  Xiangmei Chen 3,  Jun Zhan 1,  Hongquan Zhang 4
Affiliations

Affiliations

  • 1 Program for Cancer and Cell Biology, Department of Human Anatomy, Histology and Embryology, PKU International Cancer Institute, MOE Key Laboratory of Carcinogenesis and Translational Research and State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing, PR China.
  • 2 Jingjie PTM BioLab Co. Ltd., Hangzhou Economic and Technological Development Area, Hangzhou, PR China.
  • 3 Department of Microbiology & Infectious Disease Center, Peking University Health Science Center, Beijing, PR China.
  • 4 Program for Cancer and Cell Biology, Department of Human Anatomy, Histology and Embryology, PKU International Cancer Institute, MOE Key Laboratory of Carcinogenesis and Translational Research and State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing, PR China. Hongquan.Zhang@bjmu.edu.cn.
PMID: 34545082 DOI: 10.1038/s41467-021-25867-y
Abstract

Isoniazid (INH) is a first-line anti-tuberculosis drug used for nearly 70 years. However, the mechanism underlying the side effects of INH has remained elusive. Here, we report that INH and its metabolites induce a post-translational modification (PTM) of histones, lysine isonicotinylation (Kinic), also called 4-picolinylation, in cells and mice. INH promotes the biosynthesis of isonicotinyl-CoA (Inic-CoA), a co-factor of intracellular isonicotinylation. Mass spectrometry reveals 26 Kinic sites in histones in HepG2 cells. Acetyltransferases CREB-binding protein (CBP) and P300 catalyse histone Kinic, while histone deacetylase HDAC3 functions as a deisonicotinylase. Notably, MNase sensitivity assay and RNA-seq analysis show that histone Kinic relaxes chromatin structure and promotes gene transcription. INH-mediated histone Kinic upregulates PIK3R1 gene expression and activates the PI3K/Akt/mTOR signalling pathway in liver Cancer cells, linking INH to tumourigenicity in the liver. We demonstrate that Kinic is a histone acylation MARK with a pyridine ring, which may have broad biological effects. Therefore, INH-induced isonicotinylation potentially accounts for the side effects in patients taking INH long-term for anti-tuberculosis therapy, and this modification may increase the risk of Cancer in humans.

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