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.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Amino Acid Sequence
  • Animals
  • Antitubercular Agents / pharmacology*
  • Chromatin / metabolism
  • Coenzyme A / metabolism
  • HeLa Cells
  • Hep G2 Cells
  • Histone Code*
  • Histone Deacetylases / metabolism
  • Histones / chemistry
  • Histones / metabolism
  • Humans
  • Isoniazid / pharmacology*
  • Isonicotinic Acids / chemistry
  • Isonicotinic Acids / metabolism*
  • Lysine / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Neoplasms / metabolism
  • Signal Transduction / drug effects
  • Transcription, Genetic
  • Up-Regulation / drug effects
  • p300-CBP Transcription Factors / metabolism

Substances

  • Antitubercular Agents
  • Chromatin
  • Histones
  • Isonicotinic Acids
  • p300-CBP Transcription Factors
  • Histone Deacetylases
  • histone deacetylase 3
  • Lysine
  • Coenzyme A
  • Isoniazid