Abstract
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.
Highlights
Inactivation of tumor suppressor genes (TSGs) is a common characteristic in human cancer cells
In order to decipher the mechanisms of UHRF1 down-regulation, we investigated the kinetic of expression of Herpes virus-Associated Ubiquitin-Specific Protease (HAUSP), UHRF1, cleaved caspase-3 and p73 in Jurkat cells treated with thymoquinone
UHRF1 concomitantly underwent a rapid ubiquitination in response to thymoquinone and this effect was not observed in the cells expressing mutant UHRF1 Really Interesting New Gene domain (RING) domain, suggesting that UHRF1 commits an auto-ubiquitination through its RING domain in response to thymoquinone treatment
Summary
Inactivation of tumor suppressor genes (TSGs) is a common characteristic in human cancer cells. Ubiquitination-dependent degradation and epigenetic silencing are the main mechanisms involved in the regulation of TSGs [1–4]. The sole down-regulation of UHRF1 (Ubiquitin-like containing PHD and Ring Finger 1) is sufficient to allow re-expression of several TSGs including, RB1, p16INK4A, KISS1, BRCA1, RASSF1, CDKN2A and RARα [6], www.oncotarget.com meaning that all the epigenetic marks read or catalysed by UHRF1 are involved and not more. These epigenetic marks are DNA methylation, H3K9me2/3, H3R2 and putatively histone ubiquitination [7–16]. UHRF1 can be considered as a master regulator of TSGs as it coordinates DNA methylation and histone modifications at their promoters [13, 14, 17–19]
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