Date of Graduation
8-2015
Document Type
Dissertation (PhD)
Program Affiliation
Cancer Biology
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Dr. Hui-Kuan Lin
Committee Member
Dr. Xin Lin
Committee Member
Dr. Angabin Matin
Committee Member
Dr. Paul Chiao
Committee Member
Dr. Shiaw-Yih Lin
Abstract
Changes in chromatin architecture are known to be one of the underlying causes of cancer because of its ability to alter gene transcription. Histone methylation is one of the most intricate epigenetic marks because it adds multiple layers of modification on the targeted sites. Therefore, many studies have brought histone methylases and demethylases into focus, hoping to decipher their roles in cancer progression. Among these enzymes, JMJD2A is the first to shown to have demethylation activity against trimethylation, and to regulate gene expression, development, and cancer progression. While many studies have mainly focused on its role in transcriptional regulation, only recently, its non-enzymatic function has started to unveil, but the studies are scarce and inconclusive.
In our study, we showed that JMJD2A is essential in mediating activation of the canonical Wnt/β-catenin pathway, a highly conserved and complex signaling cascade that ultimately leads to nuclear accumulation of β-catenin. Nuclear β-catenin serves as a transcriptional coactivator by forming a transcriptional complex with TCF to activate Wnt target gene expressions. The presence of JMJD2A keeps β-catenin from interacting with the destruction complex components, which functions in subsequent phosphorylation and proteasomal degradation of β-catenin. JMJD2A, through maintaining the protein stability of β-catenin, affects the transcriptional activity of β-catenin and the expression of its target genes, and this is independent of the demethylase activity of JMJD2A. Surprisingly, in resting cells without Wnt ligand stimulation, JMJD2A, a supposedly nucleus-localized histone modifying protein, is mainly resided in the cytosol, and its nuclear translocation can be enhanced by active Wnt signaling.
Moreover, JMJD2A interacts with β-catenin endogenously and is required for the nuclear translocation of β-catenin upon Wnt ligand stimulation. Finally, we showed that JMJD2A has indispensable roles in cell proliferation, tumorigenesis, metastasis, and cancer stem cell traits through stabilizing β-catenin protein. Our study highlights a non-histone and non-enzymatic function of JMJD2A in the Wnt signaling pathway, and also provides cues to design inhibitors that target not only the enzyme activity but also the protein-protein interactive ability of JMJD2A.