1. Academic Validation
  2. Dynamic investigation of hypoxia-induced L-lactylation

Dynamic investigation of hypoxia-induced L-lactylation

  • Proc Natl Acad Sci U S A. 2025 Mar 11;122(10):e2404899122. doi: 10.1073/pnas.2404899122.
Jinjun Gao 1 Ruilong Liu 1 Kevin Huang 2 Ziyuan Li 3 Xinlei Sheng 1 Kasturi Chakraborty 1 Chang Han 1 Di Zhang 4 5 Lev Becker 1 Yingming Zhao 1
Affiliations

Affiliations

  • 1 Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637.
  • 2 College of Agriculture and Life Science, Cornell University, Ithaca, NY 14853.
  • 3 Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706.
  • 4 State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China.
  • 5 Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China.
Abstract

The recently identified histone modification lysine lactylation can be stimulated by L-lactate and glycolysis. Although the chemical group added upon lysine lactylation was originally proposed to be the L-enantiomer of lactate (KL-la), two isomeric modifications, lysine D-lactylation (KD-la) and N-ε-(carboxyethyl) lysine (Kce), also exist in cells, with their precursors being metabolites of glycolysis. The dynamic regulation and differences among these three modifications in response to hypoxia remain poorly understood. In this study, we demonstrate that intracellular KL-la, but not KD-la or Kce, is up-regulated in response to hypoxia. Depletion of glyoxalase Enzymes, GLO1 and GLO2, had minimal impact on KD-la, Kce, or hypoxia-induced KL-la. Conversely, blocking glycolytic flux to L-lactate under hypoxic conditions by knocking out Lactate Dehydrogenase A/B completely abolished the induction of KL-la but increased KD-la and Kce. We further observed a correlation between the level of KL-la and hypoxia-inducible factor 1 alpha (HIF-1α) expression under hypoxic conditions and when small molecules were used to stabilize HIF-1α in the normoxia condition. Our result demonstrated that there is a strong correlation between HIF-1α and KL-la in lung Cancer tissues and that patient samples with higher grade tend to have higher KL-la levels. Using a proteomics approach, we quantified 66 KL-la sites that were up-regulated by hypoxia and demonstrated that p300/CBP contributes to hypoxia-induced KL-la. Collectively, our study demonstrates that KL-la, rather than KD-la or Kce, is the prevailing lysine lactylation in response to hypoxia. Our results therefore demonstrate a link between KL-la and the hypoxia-induced adaptation of tumor cells.

Keywords

LC–MS/MS; hypoxia; lactylation; posttranslational modification (PTM).

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