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Sirtuin 2 Regulates Histone Glycation as a Semi-deglycase

Huapeng Li1,2, Yvonne Ritsema1,2, Zeng Lin1,2

  • 1Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States.

Biochemistry
|December 19, 2025
PubMed

Insights

Sirtuin 2 (SIRT2) acts as a semi-deglycase, removing acids from modified histones. This enzyme, with DJ-1, helps prevent cell damage from methylglyoxal (MGO) and glyoxal (GO) in cancer.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Methylglyoxal (MGO) and glyoxal (GO) are reactive carbonyl species implicated in cancer development.
  • MGO/GO-induced histone glycation affects chromatin structure and cancer progression.
  • Previous work identified DJ-1 and PAD4 as enzymes with glyoxalase/deglycase activities against MGO/GO-histone modifications.

Purpose of the Study:

  • To identify novel regulators of histone glycation.
  • To investigate the role of histone deacetylase SIRT2 in antagonizing MGO/GO-induced histone modifications.
  • To elucidate the mechanism by which SIRT2 modulates histone glycation.

Main Methods:

  • Biochemical assays to assess SIRT2's enzymatic activity on modified histone residues.
  • Investigating the interaction and combined function of SIRT2 and DJ-1.
  • Utilizing an enzymatically inactive DJ-1 mutant (DJ-1-C106A) in experiments.

Main Results:

  • SIRT2 identified as a "semi-deglycase" removing lactic and glycolic acids from specific histone adducts.
  • These adducts (ε-N-l-lactyllysine and hydroxyacetyllysine) are derived from MGO/GO-lysine modifications.
  • SIRT2, with DJ-1-C106A, converts MGO/GO into lactate and glycolate, mitigating cytotoxicity.

Conclusions:

  • SIRT2 is a newly discovered regulator of histone glycation.
  • SIRT2 plays a protective role against MGO and GO cytotoxicity.
  • The SIRT2-DJ-1 axis offers a potential therapeutic target for managing MGO/GO-related pathologies in cancer.

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