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Prolyl hydroxylase substrate adenylosuccinate lyase is an oncogenic driver in triple negative breast cancer

Giada Zurlo1, Xijuan Liu1, Mamoru Takada1

  • 1Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, 27599, USA.

Nature Communications
|November 16, 2019
PubMed

Insights

Researchers identified adenylosuccinate lyase (ADSL) as a key player in triple-negative breast cancer (TNBC) by uncovering its hydroxylation mechanism. This hydroxylation regulates the oncogenic cMYC pathway, impacting TNBC progression.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Protein hydroxylation is crucial for cellular functions but challenging to study due to reaction transiency.
  • Dysregulated protein hydroxylation is implicated in various diseases, including cancer.
  • Identifying hydroxylase substrates is essential for understanding disease mechanisms.

Purpose of the Study:

  • To identify novel hydroxylase substrates in triple-negative breast cancer (TNBC).
  • To elucidate the role of adenylosuccinate lyase (ADSL) hydroxylation in TNBC pathogenesis.
  • To investigate the mechanism by which ADSL hydroxylation influences the oncogenic cMYC pathway.

Main Methods:

  • Developed an enzyme-substrate trapping strategy combined with affinity purification (TAP-TAG or GST) and mass spectrometry.
  • Utilized ADSL knockout models in TNBC cell lines.
  • Performed integrated transcriptomics and metabolomics analyses.

Main Results:

  • Identified adenylosuccinate lyase (ADSL) as a substrate of EglN2 hydroxylase in TNBC.
  • Demonstrated that ADSL knockout inhibits TNBC cell proliferation and invasiveness.
  • Revealed that ADSL proline 24 hydroxylation regulates cMYC protein levels by affecting adenosine and MIR22HG expression.

Conclusions:

  • ADSL hydroxylation is a critical mechanism controlling cMYC pathway activation in TNBC.
  • ADSL hydroxylation represents a potential therapeutic target for TNBC.
  • This study provides new insights into the role of protein hydroxylation in cancer development.

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