Research Papers:

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

Abdulkhaleg Ibrahim, Mahmoud Alhosin _, Christophe Papin, Khalid Ouararhni, Ziad Omran, Mazin A. Zamzami, Abdulrahman Labeed Al-Malki, Hani Choudhry, Yves Mély, Ali Hamiche, Marc Mousli and Christian Bronner

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Oncotarget. 2018; 9:28599-28611. https://doi.org/10.18632/oncotarget.25583

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Abdulkhaleg Ibrahim1,2,*, Mahmoud Alhosin3,4,*, Christophe Papin1, Khalid Ouararhni1, Ziad Omran5, Mazin A. Zamzami3,4, Abdulrahman Labeed Al-Malki3, Hani Choudhry3,4, Yves Mély6, Ali Hamiche1, Marc Mousli6 and Christian Bronner1

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

2BioTechnology Research Center (BTRC), Tripoli, Lybia

3Department of Biochemistry, Cancer Metabolism and Epigenetic Unit, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia

4Cancer and Mutagenesis Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia

5College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia

6CNRS UMR 7021 Laboratoire de Bioimagerie et Pathologies, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France

*These authors contributed equally to this work

Correspondence to:

Mahmoud Alhosin, email: [email protected]

Christian Bronner, email: [email protected]

Keywords: apoptosis; thymoquinone; tumor suppressor genes; ubiquitination; UHRF1

Received: November 30, 2017     Accepted: May 19, 2018     Published: June 19, 2018


Down-regulation of UHRF1 (Ubiquitin-like containing PHD and Ring Finger 1) in Jurkat cells, induced by natural anticancer compounds such as thymoquinone, allows re-expression of tumor suppressor genes such as p73 and p16INK4A. In order to decipher the mechanisms of UHRF1 down-regulation, we investigated the kinetic of expression of HAUSP (herpes virus-associated ubiquitin-specific protease), UHRF1, cleaved caspase-3 and p73 in Jurkat cells treated with thymoquinone. We found that thymoquinone induced degradation of UHRF1, correlated with a sharp decrease in HAUSP and an increase in cleaved caspase-3 and p73. UHRF1 concomitantly underwent a rapid ubiquitination in response to thymoquinone and this effect was not observed in the cells expressing mutant UHRF1 RING domain, suggesting that UHRF1 commits an auto-ubiquitination through its RING domain in response to thymoquinone treatment. Exposure of cells to Z-DEVD, an inhibitor of caspase-3 markedly reduced the thymoquinone-induced down-regulation of UHRF1, while proteosomal inhibitor MG132 had no such effect. The present findings indicate that thymoquinone induces in cancer cells a fast UHRF1 auto-ubiquitination through its RING domain associated with HAUSP down-regulation. They further suggest that thymoquinone-induced UHRF1 auto-ubiquitination followed by its degradation is a key event in inducing apoptosis through a proteasome-independent mechanism.

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