Guangchao Sui Lab
YY1-Mediated Epigenetic Regulation and Its Biological Relevance to Tumorigenesis
Our research goal is to study the molecular mechanisms of tumorigenesis and develop siRNA-based therapeutic approaches to combat human cancers.
Epigenetics refers to the heritable changes of gene functions that occur without any alteration in the primary DNA sequence of the genome. Our previous work has identified YY1-regulated homeostasis of the tumor suppressor p53. In the future study, we will focus on YY1-mediated epigenetic regulation in tumor development.
Figure 1. Schematic diagram of YY1-mediated pigenetic regulation.A. YY1 mediates histone modifications by recruiting p300, HDAC and histone methyltransferase (HMT) to acetylate, deacetylate and methylate histones, respectively. B. YY1 may regulate other modifications of histone and non-histone (designated as X and Y) proteins by recruiting ubiquitin ligase (E3), deubiquitinase (DeUb) and sumo-specific protease (SENP) to its target promoters.
YY1 is a multifunctional protein. As a transcription factor, YY1 regulates the expression of many different genes, such as c-myc, c-fos, p53 and cdc6. Meanwhile, YY1 also directly interacts with many proteins with important biological functions, including p53 and Rb for tumor suppression, p300 and HDAC1 for protein acetylation and deacetylation, Mdm2 and p14ARF for p53 ubiquitination and sumoylation, Ezh2, Ezh1 and PRMT1 for histone methylation. In fact, YY1-mediated histone acetylation and deacetylation (see Figure 1A) account for YY1-regulated gene activation and repression, respectively. Moreover, as a member of polycomb group (PcG) proteins, YY1 is the only member that directly interacts with DNA at a consensus binding site to both establish and maintain gene repression. These multiple functions and unique properties endow YY1 with a pivotal role in epigenetic regulation. For example, YY1 is essential to both Ezh2-mediated histone H3(K27) methylation and PRMT1-mediated histone H4(R3) methylation. These unequivocally indicate that YY1 modulates chromatin modifications and consequently impacts the epigenetic regulation. Recently, we discovered that YY1 enhances Mdm2-mediated ubiquitination and degradation of p53. This finding revealed that YY1 is also involved in other types of protein modifications (see Figure 1B) and YY1-mediated epigenetic regulation is not just restricted to the modifications of histones.
The essential function of YY1 in epigenetic regulation likely explains its aberrant expression in different cancers. Recently, overexpressed YY1 was observed in human acute myeloid leukemia (AML), prostate cancer, breast cancer, lung cancer and osteosarcoma.
We will investigate the functional roles of the YY1-p53 and YY1-Ezh2 interplays in tumor development. Especially, we will use prostate cancer and breast cancer as our models to study the regulation of YY1-mediated mechanisms in the initiation, development and progression of these cancers. We will employ both in vivo and in vitro approaches to carry out these studies. The results of our research will provide fundamental support to the development of therapeutic approaches to conquer prostate cancer and breast cancer by reversing and correcting its epigenetic abnormality. Furthermore, due to the regulation of YY1 in various pathways and its abnormal expression observed in other cancers, our study will also provide the essential insight in the cancer development in general.