Blocking the binding of WT1 to bcl-2 promoter by G-quadruplex ligand SYUIQ-FM05

Abstract

At present, wt1, a Wilms’ tumor suppressor gene, is recognized as a critical regulator of tumorigenesis and a potential therapeutic target. WT1 shows the ability to regulate the transcription of bcl-2 by binding to a GC-rich region in the promoter, which can then fold into a special DNA secondary structure called the G-quadruplex. This function merits the exploration of the effect of a G-quadruplex ligand on the binding and subsequent regulation of WT1 on the bcl-2 promoter. In the present study, WT1 was found to bind to the double strand containing the G-quadruplex-forming sequence of the bcl-2 promoter. However, the G-quadruplex ligand SYUIQ-FM05 effectively blocked this binding by interacting with the GC-rich sequence. Our new findings are significant in the exploration of new strategies to block WT1's transcriptional regulation for cancer-cell treatment.

Site-specific amino acid substitution in dodecameric peptides determines the stability and unfolding ofc-MYCquadruplex promoting apoptosis in cancer cells

“…Chromatin immunoprecipitation studies are conducted to monitor the promoter occupancies of different transcription factors (Sp1, NM23-H2 and Nucleolin) and RNA polymerase II (RNAPII) on the region encompassing c-MYC- NHE III 1 ( 69 ). We have grown MCF-7 cells in 10-cm 2 culture flask at a density of 1 × 10 6 cells per well and treated with the synthetic peptides (FK13, KR12A, KR12B, and KR12C) for 24 hours.…”

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

“…WT1 was detected in the bone marrow of 70-80% of AML patients but not in bone marrow of healthy controls [13,14] and also suggested as a possible marker for the detection of leukemic blast cells [15]. WT1 can inhibit apoptosis in cancer cells through several mechanisms including targeting the anti-apoptotic BCL2 [5,16,17]. Like WT1, high expression levels of BCL2 were also detected in AML and considered as prognostic factor in this type of leukemia [18][19][20].…”

Specific Binding Constant and Stoichiometry Determination in Free Solution by Mass Spectrometry and Capillary Electrophoresis Frontal Analysis

“…In 2006, Dai et al discovered an intramolecular G-quadruplex formed in the promoter region of the human Bcl-2 oncogene, and it has become an attractive target for gene therapeutics ever since . The Bcl-2 oncogene is directly responsible for the expression of the Bcl-2 oncoprotein, which plays a significant role in prohibiting cell apoptosis and is overexpressed in a variety of human tumors. − Drugs that directly bind to the Bcl-2 gene promoter quadruplex can stabilize the structure of the quadruplex, eventually regulating the expression of the Bcl-2 oncoprotein. , Porphyrin derivatives , and quindoline derivatives , are among the most reported inhibitors of the Bcl-2 promoter G-quadruplex. The search for compounds that bind the Bcl-2 gene promoter quadruplex is ongoing because compounds with better specificity are always desired.…”

“…15−17 Drugs that directly bind to the Bcl-2 gene promoter quadruplex can stabilize the structure of the quadruplex, eventually regulating the expression of the Bcl-2 oncoprotein. 3,18 Porphyrin derivatives 19,20 and quindoline derivatives 21,22 are among the most reported inhibitors of the Bcl-2 promoter G-quadruplex. The search for compounds that bind the Bcl-2 gene promoter quadruplex is ongoing because compounds with better specificity are always desired.…”