Promoter demethylation of the asparagine synthetase gene is required for ATF4-dependent adaptation to asparagine depletion

J Biol Chem. 2019 Dec 6;294(49):18674-18684. doi: 10.1074/jbc.RA119.010447. Epub 2019 Oct 28.

Abstract

Tumor cells adapt to nutrient-limited environments by inducing gene expression that ensures adequate nutrients to sustain metabolic demands. For example, during amino acid limitations, ATF4 in the amino acid response induces expression of asparagine synthetase (ASNS), which provides for asparagine biosynthesis. Acute lymphoblastic leukemia (ALL) cells are sensitive to asparagine depletion, and administration of the asparagine depletion enzyme l-asparaginase is an important therapy option. ASNS expression can counterbalance l-asparaginase treatment by mitigating nutrient stress. Therefore, understanding the mechanisms regulating ASNS expression is important to define the adaptive processes underlying tumor progression and treatment. Here we show that DNA hypermethylation at the ASNS promoter prevents its transcriptional expression following asparagine depletion. Insufficient expression of ASNS leads to asparagine deficiency, which facilitates ATF4-independent induction of CCAAT-enhancer-binding protein homologous protein (CHOP), which triggers apoptosis. We conclude that chromatin accessibility is critical for ATF4 activity at the ASNS promoter, which can switch ALL cells from an ATF4-dependent adaptive response to ATF4-independent apoptosis during asparagine depletion. This work may also help explain why ALL cells are most sensitive to l-asparaginase treatment compared with other cancers.

Keywords: ATF4; CHOP; DNA methylation; acute lymphoblastic leukemia; amino acid; asparagine synthetase; cell metabolism; chromatin modification; stress response; tumor metabolism.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 4 / genetics
  • Activating Transcription Factor 4 / metabolism*
  • Asparagine / metabolism*
  • Aspartate-Ammonia Ligase / genetics
  • Aspartate-Ammonia Ligase / metabolism*
  • CCAAT-Enhancer-Binding Proteins / genetics
  • CCAAT-Enhancer-Binding Proteins / metabolism*
  • Promoter Regions, Genetic / genetics
  • RNA, Transfer / genetics
  • RNA, Transfer / metabolism

Substances

  • CCAAT-Enhancer-Binding Proteins
  • Activating Transcription Factor 4
  • Asparagine
  • RNA, Transfer
  • Aspartate-Ammonia Ligase