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c-JUN prevents methylation of p16(INK4a) (and Cdk6): the villain turned bodyguard

Karoline Kollmann1, Gerwin Heller, Veronika Sexl

  • 1Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria. Karoline. Kollmann@vetmeduni.ac.at

Oncotarget
|July 27, 2011
PubMed

Insights

The AP-1 factor c-JUN acts as a "bodyguard" by preventing epigenetic silencing of key genes like CDK6 and p16(INK4a). This novel mechanism in tumorigenesis highlights c-JUN

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • The AP-1 transcription factor c-JUN plays a role in tumorigenesis.
  • Epigenetic silencing, particularly DNA methylation, is a hallmark of cancer.
  • The cell cycle kinase CDK6 and tumor suppressor p16(INK4a) are critical in cancer development.

Purpose of the Study:

  • To elucidate the novel mechanism by which c-JUN interferes with tumorigenesis.
  • To investigate c-JUN's role in preventing epigenetic silencing of specific genes.
  • To understand how c-JUN impacts the methylation status of CDK6 and p16(INK4a) in cancer models.

Main Methods:

  • Utilized a murine leukemia model to study c-JUN's function.
  • Analyzed gene expression and methylation patterns of CDK6 and p16(INK4a) in the presence and absence of c-JUN.
  • Investigated the impact of c-JUN on the promoter regions of target genes.

Main Results:

  • c-JUN prevents the epigenetic silencing and methylation of the cell cycle kinase CDK6 in a murine leukemia model.
  • In c-JUN deficient cells, CDK6 is down-regulated due to promoter methylation, delaying leukemia formation.
  • c-JUN also protects the tumor suppressor p16(INK4a) from promoter methylation, with methylation being less frequent in cells expressing c-JUN.

Conclusions:

  • c-JUN acts as a crucial "bodyguard" by preventing the methylation and silencing of a distinct set of genes, including CDK6 and p16(INK4a), after oncogenic transformation.
  • This novel mechanism highlights c-JUN's significant role in regulating epigenetic stability and suppressing tumorigenesis.
  • The findings provide new insights into the molecular underpinnings of cancer development and potential therapeutic targets.

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