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

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...

Full description

Bibliographic Details
Main Authors: Shahad A Qadi, Mohammed A Hassan, Ryan A Sheikh, Othman AS Baothman, Mazin A Zamzami, Hani Choudhry, Abdulrahman Labeed Al-Malki, Ashwag Albukhari, Mahmoud Alhosin
Format: Article
Language:English
Published: SAGE Publishing 2019-04-01
Series:Epigenetics Insights
Online Access:https://doi.org/10.1177/2516865719839011
id doaj-a2973ebc144a45569b6a029d3772a97d
record_format Article
spelling doaj-a2973ebc144a45569b6a029d3772a97d2020-11-25T03:07:36ZengSAGE PublishingEpigenetics Insights2516-86572019-04-011210.1177/2516865719839011Thymoquinone-Induced Reactivation of Tumor Suppressor Genes in Cancer Cells Involves Epigenetic MechanismsShahad A Qadi0Mohammed A Hassan1Ryan A Sheikh2Othman AS Baothman3Mazin A Zamzami4Hani Choudhry5Abdulrahman Labeed Al-Malki6Ashwag Albukhari7Mahmoud Alhosin8Biochemistry Department, Faculty of Science, King Abdulaziz University, Jeddah, Saudi ArabiaDepartment of Basic Medical Sciences, College of Medicine and Health Sciences, Hadhramout University, Mukalla, YemenBiochemistry Department, Faculty of Science, King Abdulaziz University, Jeddah, Saudi ArabiaBiochemistry Department, Faculty of Science, King Abdulaziz University, Jeddah, Saudi ArabiaCancer and Mutagenesis Unit, King Fahd Center for Medical Research, King Abdulaziz University, Jeddah, Saudi ArabiaCancer and Mutagenesis Unit, King Fahd Center for Medical Research, King Abdulaziz University, Jeddah, Saudi ArabiaBiochemistry Department, Faculty of Science, King Abdulaziz University, Jeddah, Saudi ArabiaCancer and Mutagenesis Unit, King Fahd Center for Medical Research, King Abdulaziz University, Jeddah, Saudi ArabiaCancer and Mutagenesis Unit, King Fahd Center for Medical Research, King Abdulaziz University, Jeddah, Saudi ArabiaThe 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.https://doi.org/10.1177/2516865719839011
collection DOAJ
language English
format Article
sources DOAJ
author Shahad A Qadi
Mohammed A Hassan
Ryan A Sheikh
Othman AS Baothman
Mazin A Zamzami
Hani Choudhry
Abdulrahman Labeed Al-Malki
Ashwag Albukhari
Mahmoud Alhosin
spellingShingle Shahad A Qadi
Mohammed A Hassan
Ryan A Sheikh
Othman AS Baothman
Mazin A Zamzami
Hani Choudhry
Abdulrahman Labeed Al-Malki
Ashwag Albukhari
Mahmoud Alhosin
Thymoquinone-Induced Reactivation of Tumor Suppressor Genes in Cancer Cells Involves Epigenetic Mechanisms
Epigenetics Insights
author_facet Shahad A Qadi
Mohammed A Hassan
Ryan A Sheikh
Othman AS Baothman
Mazin A Zamzami
Hani Choudhry
Abdulrahman Labeed Al-Malki
Ashwag Albukhari
Mahmoud Alhosin
author_sort Shahad A Qadi
title Thymoquinone-Induced Reactivation of Tumor Suppressor Genes in Cancer Cells Involves Epigenetic Mechanisms
title_short Thymoquinone-Induced Reactivation of Tumor Suppressor Genes in Cancer Cells Involves Epigenetic Mechanisms
title_full Thymoquinone-Induced Reactivation of Tumor Suppressor Genes in Cancer Cells Involves Epigenetic Mechanisms
title_fullStr Thymoquinone-Induced Reactivation of Tumor Suppressor Genes in Cancer Cells Involves Epigenetic Mechanisms
title_full_unstemmed Thymoquinone-Induced Reactivation of Tumor Suppressor Genes in Cancer Cells Involves Epigenetic Mechanisms
title_sort thymoquinone-induced reactivation of tumor suppressor genes in cancer cells involves epigenetic mechanisms
publisher SAGE Publishing
series Epigenetics Insights
issn 2516-8657
publishDate 2019-04-01
description 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.
url https://doi.org/10.1177/2516865719839011
work_keys_str_mv AT shahadaqadi thymoquinoneinducedreactivationoftumorsuppressorgenesincancercellsinvolvesepigeneticmechanisms
AT mohammedahassan thymoquinoneinducedreactivationoftumorsuppressorgenesincancercellsinvolvesepigeneticmechanisms
AT ryanasheikh thymoquinoneinducedreactivationoftumorsuppressorgenesincancercellsinvolvesepigeneticmechanisms
AT othmanasbaothman thymoquinoneinducedreactivationoftumorsuppressorgenesincancercellsinvolvesepigeneticmechanisms
AT mazinazamzami thymoquinoneinducedreactivationoftumorsuppressorgenesincancercellsinvolvesepigeneticmechanisms
AT hanichoudhry thymoquinoneinducedreactivationoftumorsuppressorgenesincancercellsinvolvesepigeneticmechanisms
AT abdulrahmanlabeedalmalki thymoquinoneinducedreactivationoftumorsuppressorgenesincancercellsinvolvesepigeneticmechanisms
AT ashwagalbukhari thymoquinoneinducedreactivationoftumorsuppressorgenesincancercellsinvolvesepigeneticmechanisms
AT mahmoudalhosin thymoquinoneinducedreactivationoftumorsuppressorgenesincancercellsinvolvesepigeneticmechanisms
_version_ 1724669551385247744