DOI
https://doi.org/10.25772/BB9B-BK79
Author ORCID Identifier
https://orcid.org/0000-0001-6660-1296
Defense Date
2022
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Clinical and Translational Sciences
First Advisor
Dr. Devanand Sarkar
Abstract
Amplification of chromosome 8q, which harbors the driver oncogene MYC, is a frequent event in hepatocellular carcinoma (HCC). We identified that TATA-box Binding Protein Associated Factor 2 (TAF2), a component of Transcription Factor IID (TFIID), is the most frequently co-amplified gene with MYC in HCC. A potential oncogenic function of TAF2 in HCC has not been established. Bioinformatic analysis shows amplification, increase in copy number and mRNA overexpression of TAF2 in HCC patients. A significant negative correlation between TAF2 levels and overall survival of HCC patients was observed. We identified TAF2 overexpression in human HCC cells and tissue samples, compared to their normal counterparts. In vivo, TAF2 overexpression did not induce tumors, MYC overexpression induced moderate HCC, and combined overexpression of TAF2 and MYC generated robust HCC. RNA-sequencing revealed that combined overexpression of TAF2 and MYC did not affect the expression of genes upregulated by MYC, but caused further inhibition of genes downregulated by MYC. Many of these downregulated genes are bona fide tumor suppressors indicating that TAF2 cooperates with MYC to inhibit tumor suppressor genes. Knockdown of TAF2 in human HCC cell lines did not affect proliferation, but significantly decreased their ability to invade and migrate, which was associated with inhibition of Rho signaling, and decreased activity of matrix metalloproteases (MMPs), MMP2 and MMP9. This is the first study documenting an oncogenic function of TAF2 and cooperation of TAF2 and MYC to promote HCC, paving the way for a potential therapeutic strategy of combined inhibition of these two genes.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
12-16-2022