GCN5 HAT inhibition reduces human Burkitt lymphoma cell survival through reduction of MYC target gene expression and impeding BCR signaling pathways

Aimee T. Farria, Lisa Maria Mustachio, Zeynep H. Coban Akdemir, Sharon Y.R. Dent

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5847-5858
Number of pages12
JournalOncotarget
Volume10
Issue number56
StatePublished - Oct 1 2019

Fingerprint

Burkitt Lymphoma
Cell Survival
Gene Expression
Lymphoma
B-Lymphocytes
Down-Regulation
Genes
Cell Line
Acetyltransferases
Critical Pathways
Acetylation
Phosphatidylinositol 3-Kinases
Histones
Non-Hodgkin's Lymphoma
Lysine
Chromatin
Catalytic Domain
Transcription Factors
Cell Proliferation
Apoptosis

Keywords

  • BCR
  • GCN5
  • MYC
  • lymphoma

ASJC Scopus subject areas

  • Oncology

Cite this

GCN5 HAT inhibition reduces human Burkitt lymphoma cell survival through reduction of MYC target gene expression and impeding BCR signaling pathways. / Farria, Aimee T.; Mustachio, Lisa Maria; Coban Akdemir, Zeynep H.; Dent, Sharon Y.R.

In: Oncotarget, Vol. 10, No. 56, 01.10.2019, p. 5847-5858.

Research output: Contribution to journalArticle

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AU - Dent, Sharon Y.R.

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