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Thymoquinone challenges UHRF1 to commit auto-ubiquitination: a key event for apoptosis induction in cancer cells

Abdulkhaleg Ibrahim1,2, Mahmoud Alhosin3,4, Christophe Papin1

  • 1Institut De Génétique Et De Biologie Moléculaire Et Cellulaire (IGBMC), INSERM U1258 CNRS UMR 7104, Université de Strasbourg, Illkirch, France.

Oncotarget
|July 10, 2018
PubMed

Insights

Thymoquinone triggers cancer cell apoptosis by causing rapid auto-ubiquitination and degradation of UHRF1 (Ubiquitin-like containing PHD and Ring Finger 1) via a caspase-3 dependent pathway.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Biochemistry

Background:

  • UHRF1 (Ubiquitin-like containing PHD and Ring Finger 1) down-regulation by natural compounds like thymoquinone can restore tumor suppressor gene expression.
  • Understanding the precise mechanisms of UHRF1 regulation is crucial for developing novel cancer therapies.

Purpose of the Study:

  • To investigate the molecular mechanisms by which thymoquinone induces UHRF1 down-regulation in Jurkat cells.
  • To elucidate the role of HAUSP, caspase-3, and UHRF1 auto-ubiquitination in this process.

Main Methods:

  • Kinetic analysis of HAUSP, UHRF1, cleaved caspase-3, and p73 expression in Jurkat cells treated with thymoquinone.
  • Assessment of UHRF1 ubiquitination using a mutant UHRF1 RING domain.
  • Evaluation of UHRF1 down-regulation in the presence of caspase-3 inhibitor (Z-DEVD) and proteasomal inhibitor (MG132).

Main Results:

  • Thymoquinone treatment led to UHRF1 degradation, decreased HAUSP levels, and increased cleaved caspase-3 and p73.
  • UHRF1 underwent rapid auto-ubiquitination through its RING domain in response to thymoquinone, a process dependent on caspase-3 activity.
  • Proteasomal degradation was not involved in thymoquinone-induced UHRF1 down-regulation.

Conclusions:

  • Thymoquinone induces rapid UHRF1 auto-ubiquitination and degradation in cancer cells via a caspase-3 dependent, proteasome-independent pathway.
  • This mechanism, involving HAUSP down-regulation, is a key event in thymoquinone-induced apoptosis.
Keywords:
UHRF1apoptosisthymoquinonetumor suppressor genesubiquitination

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