Thymoquinone-Induced Reactivation of Tumor Suppressor Genes in Cancer Cells Involves Epigenetic Mechanisms

Abstract

The epigenetic silencing of tumor suppressor genes (TSGs) is a common finding in several solid and hematological tumors involving various epigenetic readers and writers leading to enhanced cell proliferation and defective apoptosis. Thymoquinone (TQ), the major biologically active compound of black seed oil, has demonstrated anticancer activities in various tumors by targeting several pathways. However, its effects on the epigenetic code of cancer cells are largely unknown. In the present study, we performed RNA sequencing to investigate the anticancer mechanisms of TQ-treated T-cell acute lymphoblastic leukemia cell line (Jurkat cells) and examined gene expression using different tools. We found that many key epigenetic players, including ubiquitin-like containing plant homeodomain (PHD) and really interesting new gene (RING) finger domains 1 ( UHRF1), DNMT1,3A,3B, G9A, HDAC1,4,9, KDM1B , and KMT2A,B,C,D,E , were downregulated in TQ-treated Jurkat cells. Interestingly, several TSGs, such as DLC1, PPARG, ST7, FOXO6, TET2, CYP1B1, SALL4 , and DDIT3 , known to be epigenetically silenced in various tumors, including acute leukemia, were upregulated, along with the upregulation of several downstream pro-apoptotic genes, such as RASL11B, RASD1, GNG3, BAD , and BIK . Data obtained from RNA sequencing were confirmed using quantitative reverse transcription polymerase chain reaction (RT-qPCR) in Jurkat cells, as well as in a human breast cancer cell line (MDA-MB-468 cells). We found that the decrease in cell proliferation and in the expression of UHRF1, DNMT1, G9a , and HDAC1 genes in both cancer cell (Jurkat cells and MDA-MB-468 cells) lines depends on the TQ dose. Our results indicate that the use of TQ as an epigenetic drug represents a promising strategy for epigenetic therapy for both solid and blood tumors by targeting both DNA methylation and histone post-translational modifications.

Extra Virgin Olive Oil and Nigella sativa Oil Produced in Central Italy: A Comparison of the Nutrigenomic Effects of Two Mediterranean Oils in a Low-Grade Inflammation Model

“…This is consistent with previous investigations suggesting that thymoquinone could reverse DNA hypermethylation in cancer cells [44,45]. Another recent study demonstrated that thymoquinone can decrease the expression of some important epigenetic proteins like DNMT1,3A,3B and HDAC1 in Jurkat cells and breast cancer cells [46]. In fact, it has been recently speculated that because of its structure, thymoquinone could act as both a demethylating and methylating agent [45].…”

Chemopreventive and Anticancer Effects of Thymoquinone: Cellular and Molecular Targets

“…TQ-mediated anticancer activity has also been shown to involve epigenetic suppression or activation of specific genes [57,146,147]. TQ-induced p73 has been shown to represses the expression of the anti-apoptotic epigenetic integrator known as ubiquitin-like-containing PHD and RING finger domains (UHRF1) and its partner DNA methyltransferase 1 (DNMT1) [57,69].…”

Thymoquinone induces cell proliferation inhibition and apoptosis in acute myeloid leukemia cells: role of apoptosis-related WT1 and BCL2 genes

“…Many purified components extracted from medicinal plants have shown beneficial therapeutic potentials in the recent years and widely used as an alternative to chemical drugs. Thymoquinone (TQ), the major bioactive component of the essential oil of black seeds have shown promising inhibitory effects on a large number of solid and leukemia tumors through targeting several pathways such as those involved in cell cycle, apoptosis, ROS generation, metastasis and angiogenesis [21][22][23][24][25][26].…”