Publication Date
2020
Document Type
Dissertation
Committee Members
Madhavi Kadakia, Ph.D. (Advisor); Thomas L. Brown, Ph.D. (Committee Chair); Paula A. Bubulya, Ph.D. (Committee Member); Weiwen Long, Ph.D. (Committee Member); Michael P. Markey, Ph.D. (Committee Member)
Degree Name
Doctor of Philosophy (PhD)
Abstract
ΔNp63α is a p53 transcription factor family member that promotes cellular proliferation and survival. In squamous cell carcinoma (SCC), ΔNp63α overexpression is associated with poor prognosis and survival, implicating it as a proto-oncogene. Despite its importance in SCC, the mechanisms regulating ΔNp63α expression are poorly understood. We have identified the acetyltransferase TIP60 as a novel upstream regulator of ΔNp63α levels. We discovered that TIP60 regulates ΔNp63α via two mechanisms. First, TIP60 upregulates ΔNp63α mRNA levels. Moreover, pharmacological inhibition of TIP60 activity reduces ΔNp63α transcript levels, indicating that TIP60-cataltyic activity is vital to amplified transcription of ΔNp63α. Second, we have demonstrated that TIP60 promotes ΔNp63α protein stability by preventing its ubiquitination and proteasomal degradation. This study further shows that TIP60 co-localizes with, interacts with, and directly acetylates ΔNp63α. Utilizing mass spectrometry and site directed mutagenesis, we found that TIP60 acetylates ΔNp63α residues K138, K139, and K494, respectively. We additionally revealed that preventing acetylation of these sites inhibit TIP60-mediated stabilization of ΔNp63α, providing evidence that acetylation by TIP60 enhances ΔNp63α protein stability. We further investigated the functions of the TIP60-ΔNp63α axis in the regulation of SCC proliferation. We discovered that regulation of ΔNp63α by TIP60 increases cellular proliferation. In accordance with the functional role of ΔNp63α, pharmacological inhibition of TIP60 reduced SCC cell proliferation suggesting TIP60 may have therapeutic potential in cancers exhibiting ΔNp63α overexpression. Furthermore, we investigated the mechanisms by which TIP60 regulation of ΔNp63α enhances cancer cell proliferation. We discovered that TIP60 upregulation of ΔNp63α represses p21Cip1/Waf1 levels, resulting in increased G2/M progression. In conclusion, this study uncovers a novel mechanism promoting ΔNp63α-mediated cellular proliferation in SCC. These findings may be critical for designing new therapeutic strategies for the treatment of SCC by targeting ΔNp63α expression and activity.
Page Count
155
Department or Program
Biomedical Sciences
Year Degree Awarded
2020
Copyright
Copyright 2020, all rights reserved. My ETD will be available under the "Fair Use" terms of copyright law.
ORCID ID
0000-0002-7528-2810
