p63(alpha) belongs to the p53-family of proteins and has full-length (TA) as well as truncated ((delta)N) p63(alpha) isoforms. Previous studies have shown that TA and (delta)Np63(alpha) play multiple roles in cancer and development. In cancer, (delta)Np63(alpha)-mediated transcriptional repression promotes oncogenesis while transactivation by TAp63(alpha) is critical during development. Despite their importance, little is known regarding how TA or (delta)Np63(alpha) is regulated and factors influencing the function of p63(alpha) have yet to be identified.
Here, I identify Special AT-rich Binding Protein 2 (SATB2) as a protein that forms a complex with and modulates the function of p63(alpha). SATB2 is detected in multiple head and neck squamous cell carcinoma (HNSCC) cell lines that also show overexpression of (delta)Np63(alpha). Histological analysis on tumor specimens revealed that SATB2 is predominantly expressed in advanced-stage HNSCC cancers. SATB2 increases DNA-binding capabilities of (delta)Np63(alpha), augmenting (delta)Np63(alpha) repression of apoptotic gene expression. Knockdown of SATB2 in HNSCC cells sensitizes cancer cells towards chemotherapy- and radiation-induced apoptosis. These results indicate that SATB2 functions as a co-factor and promotes the transrepression function of (delta)Np63(alpha) in HNSCC.
In addition to examining the role of SATB2 in HNSCC, I also investigated the effect of SATB2 on the ability of TAp63(alpha) to induce gene expression. In particular, perp has been shown to be a critical downstream target of p63 during development. ChIP analysis revealed that while SATB2 increases TAp63(alpha)-binding to apoptotic gene promoters, SATB2 decreases TAp63(alpha) localization on the perp promoter and inhibits p63(alpha)-mediated perp induction. SATB2 more readily interacts with human disease-associated p63(alpha) mutations that are found in the SAM domain, further inhibiting transcriptional properties of these mutants. Together, my results suggest that SATB2 is an important modulator of p63(alpha) in cancer and development.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/36209 |
| Date | 14 August 2013 |
| Creators | Chung, Jacky |
| Contributors | Kaplan, David, Irwin, Meredith |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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