The Role of the ING3 Epigenetic Regulator in Prostate Cancer
Abstract
INhibitor of growth (ING) proteins are epigenetic regulators and stoichiometric members of histone acetyltransferase (KAT) or histone deacetylase (KDAC) complexes. By reading the histone mark H3K4me3, they direct their complexes to chromatin to alter gene expression. This thesis focuses on the role of ING3 in prostate cancer biology.
Since rigorous characterization of antibodies is a prerequisite to acquire reliable results, we began by characterizing a new mouse monoclonal antibody against ING3. We profiled the expression of ING3 protein in normal human tissues and found that it is highly expressed in bone marrow, suggesting high expression in hematopoietic cell precursors. We also reported that ING3 protein levels are highest in proliferating tissues of the small intestine and epidermis. These data suggest a role for ING3 in promoting cell growth and renewal.
In the second part of this study, we investigated the effects of ING3 on the androgen receptor (AR) pathway in prostate cancer (PC). We hypothesized that ING3 by virtue of being an essential member of TIP60 KAT complex, plays a role in post-translational modifications of AR protein and thereby contributes to PC progression. We found that the levels of ING3 and AR are positively correlated in patient samples and cell lines. ING3 potentiates androgen effects, activating expression of androgen responsive genes and AR-regulated reporters. We showed that ING3 interacts with the binding domain of AR and this interaction happens in the cytoplasm in the absence of androgens. ING3 increases AR-TIP60 interaction, promoting AR acetylation and nuclear translocation. The activating role of ING3 is independent of its ability to target the TIP60 complex to H3K4me3, identifying a previously unknown function for ING3. Knockdown of ING3 inhibits PC cell proliferation and migration, establishing ING3 as a positive regulator of growth in PC.
Lastly, we asked whether ING3 could serve as a biomarker to distinguish latent versus aggressive PC. ING3 levels are higher in aggressive PC, with high levels of ING3 predicting shorter overall survival. Analysis with other predictive factors shows that including ING3 levels provides more accurate prognosis in PC.
Description
Keywords
Biology--Cell, Biology--Molecular, Oncology
Citation
Nabbi, A. (2017). The Role of the ING3 Epigenetic Regulator in Prostate Cancer (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/28360