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Thymoquinone Enhances Apoptosis of K562 Chronic Myeloid Leukemia Cells through Hypomethylation of <i>SHP-1</i> and Inhibition of JAK/STAT Signaling Pathway

The epigenetic silencing of tumor suppressor genes (TSGs) is critical in the development of chronic myeloid leukemia (CML). <i>SHP-1</i> functions as a TSG and negatively regulates JAK/STAT signaling. Enhancement of <i>SHP-1</i> expression by demethylation provides molecular...

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Main Authors: Futoon Abedrabbu Al-Rawashde (Author), Ola M. Al-Sanabra (Author), Moath Alqaraleh (Author), Ahmad Q. Jaradat (Author), Abdullah Saleh Al-Wajeeh (Author), Muhammad Farid Johan (Author), Wan Rohani Wan Taib (Author), Imilia Ismail (Author), Hamid Ali Nagi Al-Jamal (Author)
Format: Book
Published: MDPI AG, 2023-06-01T00:00:00Z.
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Summary:The epigenetic silencing of tumor suppressor genes (TSGs) is critical in the development of chronic myeloid leukemia (CML). <i>SHP-1</i> functions as a TSG and negatively regulates JAK/STAT signaling. Enhancement of <i>SHP-1</i> expression by demethylation provides molecular targets for the treatment of various cancers. Thymoquinone (TQ), a constituent of <i>Nigella sativa</i> seeds, has shown anti-cancer activities in various cancers. However, TQs effect on methylation is not fully clear. Therefore, the aim of this study is to assess TQs ability to enhance the expression of <i>SHP-1</i> through modifying DNA methylation in K562 CML cells. The activities of TQ on cell cycle progression and apoptosis were evaluated using a fluorometric-red cell cycle assay and Annexin V-FITC/PI, respectively. The methylation status of <i>SHP-1</i> was studied by pyrosequencing analysis. The expression of <i>SHP-1</i>, <i>TET2</i>, <i>WT1</i>, <i>DNMT1</i>, <i>DNMT3A</i>, and <i>DNMT3B</i> was determined using RT-qPCR. The protein phosphorylation of STAT3, STAT5, and JAK2 was assessed using Jess Western analysis. TQ significantly downregulated the <i>DNMT1</i> gene, <i>DNMT3A</i> gene, and <i>DNMT3B</i> gene and upregulated the <i>WT1</i> gene and <i>TET2</i> gene. This led to hypomethylation and restoration of <i>SHP-1</i> expression, resulting in inhibition of JAK/STAT signaling, induction of apoptosis, and cell cycle arrest. The observed findings imply that TQ promotes apoptosis and cell cycle arrest in CML cells by inhibiting JAK/STAT signaling via restoration of the expression of JAK/STAT-negative regulator genes.
Item Description:10.3390/ph16060884
1424-8247

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