TY - JOUR
T1 - Thymoquinone challenges UHRF1 to commit auto-ubiquitination
T2 - A key event for apoptosis induction in cancer cells
AU - Ibrahim, Abdulkhaleg
AU - Alhosin, Mahmoud
AU - Papin, Christophe
AU - Ouararhni, Khalid
AU - Omran, Ziad
AU - Zamzami, Mazin A.
AU - Al-Malki, Abdulrahman Labeed
AU - Choudhry, Hani
AU - Mély, Yves
AU - Hamiche, Ali
AU - Mousli, Marc
AU - Bronner, Christian
N1 - Publisher Copyright:
©Ibrahim et al.
PY - 2018/6/19
Y1 - 2018/6/19
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Thymoquinone
KW - Tumor suppressor genes
KW - UHRF1
KW - Ubiquitination
UR - http://www.scopus.com/inward/record.url?scp=85048738622&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.25583
DO - 10.18632/oncotarget.25583
M3 - Article
C2 - 29983883
AN - SCOPUS:85048738622
SN - 1949-2553
VL - 9
SP - 28599
EP - 28611
JO - Oncotarget
JF - Oncotarget
IS - 47
ER -