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Hypoxia-mediated regulation of DDX5 through decreased chromatin accessibility and post-translational targeting

Katarzyna B Leszczynska1,2, Monika Dzwigonska2, Hala Estephan1

  • 1Department of Oncology, Oxford Institute for Radiation Oncology, The University of Oxford, UK.

Molecular Oncology
|April 4, 2023
PubMed

Insights

Hypoxia, a common tumor condition, decreases chromatin accessibility and represses genes like DDX5. This repression limits R-loop accumulation, suggesting a role for reduced RNA helicase activity in tumor progression.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cellular Response to Microenvironment

Background:

  • Local hypoxia is prevalent in solid tumors, correlating with disease aggressiveness and treatment resistance.
  • Gene expression alterations are key to the cellular response to hypoxia, yet research often overlooks downregulated genes.
  • Understanding genes repressed by hypoxia is crucial for deciphering tumor biology and developing targeted therapies.

Purpose of the Study:

  • To investigate changes in chromatin accessibility and gene expression under hypoxic conditions.
  • To identify specific pathways and genes, such as DDX5 (RNA helicase), that are downregulated during hypoxia.
  • To elucidate the functional role of hypoxia-mediated repression of DDX5 in regulating R-loop accumulation and replication stress.

Main Methods:

  • Analysis of chromatin accessibility in hypoxic versus normoxic conditions.
  • Gene expression profiling in cancer cell lines, tumor xenografts, and patient samples.
  • Functional rescue experiments to assess the impact of DDX5 restoration in hypoxia.
  • Quantification of R-loop levels and replication stress markers.

Main Results:

  • Hypoxia leads to decreased chromatin accessibility, particularly at gene promoters, affecting DNA repair and splicing pathways.
  • DDX5 expression is significantly reduced in hypoxic cancer cells, tumors, and patient samples.
  • Restoring DDX5 expression in hypoxic conditions exacerbates replication stress and R-loop accumulation.
  • Hypoxia-mediated repression of DDX5 acts as a mechanism to restrict R-loop accumulation.

Conclusions:

  • Hypoxia actively represses genes involved in R-loop processing, including the RNA helicase DDX5.
  • The downregulation of DDX5 in hypoxia plays a specific role in limiting R-loop accumulation, potentially influencing tumor progression.
  • These findings highlight the importance of studying downregulated genes in hypoxia and their distinct roles in cancer biology.
Keywords:
ATACseqDDX5R-loopshypoxia

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