Author ORCID Identifier
0000-0002-3524-8730
Date of Graduation
8-2019
Document Type
Dissertation (PhD)
Program Affiliation
Epigenetics and Molecular Carcinogenesis
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Sharon Dent, PhD
Committee Member
Marcelo Aldaz, MD, PhD
Committee Member
Shawn Bratton, PhD
Committee Member
Taiping Chen, PhD
Committee Member
Rick Finch, PhD
Abstract
GCN5 is the catalytic subunit in the acetyltransferase module of SAGA and ATAC, multiprotein complexes involved in the modification of histone and nonhistone proteins. GCN5 is most recognized as a co-activator of gene transcription. The SAGA complex is recruited to chromatin by transcription factors such as MYC and E2F1 where GCN5 acetylates H3K9 leading to a more open and accessible chromatin structure. Previous research has demonstrated that GCN5 also acetylates MYC, a protein that amplifies the expression of cancer-promoting genes and is frequently dysregulated in cancer, increasing its stability. Our lab has found there is a significant overlap in the target genes of GCN5 and c-MYC in mouse embryonic stem cells. Recent studies have also implicated GCN5 in enhancing progression of several different cancers. We hypothesize that GCN5 functions are also linked to those of MYC isoforms in cancer.
Triple negative breast cancers typically overexpress c-MYC and these cancers are difficult to treat by traditional therapies. We hypothesize that inhibition or depletion of GCN5 will reduce c-MYC target gene expression and therefore reduce the cancer promoting effects of this oncoprotein. Our data shows that depletion of ix GCN5 reduces many characteristic aspects of oncogenic transformation in breast cancer cells, including growth, invasion, and migration. Loss of GCN5 in these cells also impacts the expression of genes associated with epithelial-to-mesenchymal transition (EMT). Xenograft experiments indicate that loss of GCN5 reduces the invasion of these cancer cells in vivo. Based on these data, we will define specific function(s) of GCN5 that are necessary for the maintenance of the cancer phenotype in Triple negative breast cancer cells.
Burkitt lymphoma is an aggressive subtype of Non-Hodgkin’s lymphoma driven by the overexpression of c-MYC. In this dissertation we show inhibition of GCN5 reduces MYC-driven gene expression in Burkitt lymphoma and therefore reduces cancer phenotypes seen in aggressive lymphoid cancer cells. We used the Eμ-Myc mouse model, which develops a Burkitt-like lymphoma, in order to define the effects of GCN5 loss in MYC driven cancers in mice. GCN5 Flox/Flox mice were crossed with Eμ-Myc transgenic mice, as well as the B cell specific CD-19 Cre mice in order to delete GCN5. Our data indicate a significant trend of increased survival of Eμ-Myc mice upon loss of GCN5 in B cells. Gene expression analysis showed that GCN5 influences cell cycle regulation in MYC overexpressing B cells. Overall, our data indicate that loss of GCN5 has a significant impact on the formation and progression of MYC driven cancers.
Keywords
SAGA, GCN5, acetylation, breast cancer, lymphoma, chromatin-modifying complex, BCR