GCN5 HAT inhibition reduces human Burkitt lymphoma cell survival through reduction of MYC target gene expression and impeding BCR signaling pathways
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Aimee T. Farria1,2,3, Lisa Maria Mustachio1,2, Zeynep H. Coban Akdemir4 and Sharon Y.R. Dent1,2
1 Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas 78957, USA
2 The Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Smithville, Texas 78957, USA
3 Program in Genetics and Epigenetics, The University of Texas MD Anderson Cancer Center, UT Health Graduate School of Biomedical Sciences, Houston, Texas 77030, USA
4 Departments of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA
|Sharon Y.R. Dent,||email:||firstname.lastname@example.org|
Keywords: GCN5; MYC; lymphoma; BCR
Received: July 09, 2019 Accepted: September 10, 2019 Published: October 08, 2019
GCN5, the catalytic subunit in the acetyltransferase modules of SAGA and ATAC, functions as a coactivator of gene transcription. The SAGA complex is recruited to chromatin by transcription factors such as MYC and E2F1 to facilitate acetylation of histones, especially H3 at lysine 9 (H3K9). Burkitt lymphoma is an aggressive subtype of Non-Hodgkin lymphoma driven by the overexpression of MYC. Comparison of GCN5 expression in normal human B cells versus human Burkitt Lymphoma cell lines indicates overexpression of GCN5 in lymphoma. Treatment of Burkitt lymphoma cell lines with a specific inhibitor indicates that decreased GCN5 HAT activity reduces viability and proliferation of these cells. Inhibition of GCN5 HAT activity also induces apoptosis in lymphoma cells. Expression of MYC target genes as well as genes associated with B cell receptor signaling are significantly downregulated upon inhibition of GCN5 enzymatic activity. This downregulation leads to diminished PI3K signaling, a critical pathway in lymphomagenesis. Our data indicate that inhibition of GCN5 HAT activity reduces the tumorigenic properties of human Burkitt lymphoma cells by attenuating BCR signaling and that GCN5 may be a viable target for lymphoma drug therapy.
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