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Targeted downregulation of MYC through G‐quadruplex stabilization: a novel therapeutic approach for breast cancer and lymphoma
Author(s) -
Chang Katarina T.,
Hao Taisen,
DeSouza Harriet EJ.,
Brooks Tracy Ann
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.826.14
Subject(s) - druggability , cancer research , transcription factor , breast cancer , lymphoma , biology , downregulation and upregulation , cancer cell , transcription (linguistics) , promoter , raji cell , chemistry , oligonucleotide , brd4 , microbiology and biotechnology , cancer , dna , gene , gene expression , biochemistry , genetics , immunology , histone , bromodomain , linguistics , philosophy
MYC, a basic helix‐loop‐helix/leucine zipper transcription factor, is an enigmatic protein with over 30,000 potential binding sites in the human genome, 10–15% of which are generally bound at any one time. It was one of the first proto‐oncogenes to be described and is ultimately disregulated in most tumor types and stages, including estrogen receptor (ER)‐positive breast cancer and non‐Hodgkin's lymphoma. Decreased MYC expression has been shown to significantly impact tumor viability while offering a notable therapeutic window and overall safe profile. As we and other groups have shown, stabilization of the higher order genomic structure – the G‐quadruplex (G4) – in the MYC promoter is an established approach to decreasing transcription and facilitating tumor lysis. We have pioneered a DNA interference (DNAi) approach to take advantage of the “druggability” of the DNA structure, and have previously demonstrated the specificity and efficacy of oligonucleotide (ODN)‐mediated stabilization of the predominant G4 structure within the MYC promoter. In the current report, we further optimize the DNAi, including the evaluation of different ODN lengths, for specifically stabilizing the MYC promoter G4 (as demonstrated by EMSA and chemical footprinting) and modulating promoter activity. The lead DNAi (A‐18) demonstrates anti‐cancer activity in RAJI and CA46 Burkitt's lymphoma cells, and in ER+ MCF‐7 breast cancer cells. Moreover, A‐18 enters the nuclei of cancer cells, where it binds the G4‐forming region of the MYC promoter, in an inducible manner. This clamp has potential as a novel DNAi therapeutic. It is being further explored for its ability to sensitize cancer cells to chemotherapeutic agents, and its formulation for delivery in nanotherapeutic vehicles. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .