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JAK2 regulates mismatch repair protein-mediated epigenetic alterations in response to oxidative damage

Ning Ding1, Sam A Miller1,2, Sudha S Savant1

  • 1Medical Sciences, Indiana University School of Medicine, Bloomington, Indiana.

Environmental and Molecular Mutagenesis
|December 15, 2018
PubMed

Insights

Chronic inflammation and oxidative stress trigger aberrant DNA methylation in epithelial cells, promoting cancer. Janus kinase 2 (JAK2) activation by hydrogen peroxide links kinase activity to epigenetic silencing of tumor suppressor genes.

Area of Science:

  • Epigenetics
  • Molecular Biology
  • Cancer Research

Background:

  • Chronic inflammation causes DNA methylation changes, contributing to cancer.
  • Reactive oxygen species (ROS) induce oxidative DNA damage and epigenetic alterations.
  • MSH2/MSH6 proteins recruit DNMT1 and PRC2 to DNA damage sites, repressing tumor suppressor genes (TSGs).

Purpose of the Study:

  • To identify the specific signal linking ROS to MSH2/MSH6 chromatin binding.
  • To investigate the role of Janus kinase 2 (JAK2) in oxidative stress-induced epigenetic alterations.

Main Methods:

  • Investigated the interaction of JAK2 with MSH2/MSH6 in response to hydrogen peroxide (H2O2).
  • Utilized JAK2 inhibition/knockdown to assess effects on MSH2/MSH6, DNMT1, PRC2, and H3K27me3.
  • Examined transcriptional repression of TSGs and correlated JAK2 mRNA with CIMP in colorectal cancer.

Main Results:

  • Hydrogen peroxide (H2O2) induces nuclear localization and interaction of JAK2 with MSH2 and MSH6.
  • JAK2 inhibition/knockdown reduces H2O2-induced chromatin binding of MSH2, MSH6, DNMT1, PRC2, and H3K27me3.
  • JAK2 activity is essential for oxidative damage-induced TSG repression; JAK2 mRNA correlates with CIMP in colorectal cancer.

Conclusions:

  • JAK2 activation is a key mediator of oxidative stress-induced epigenetic silencing of tumor suppressor genes.
  • Findings reveal a novel link between kinase signaling and epigenetic dysregulation in inflammation-driven tumorigenesis.
  • JAK2 may represent a therapeutic target for cancers associated with oxidative stress and aberrant DNA methylation.
Keywords:
DNMT1EZH2JAK2MSH2MSH6oxidative damage

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