DNA methylation and histone deacetylation are distinct biochemical processes that control gene expression. While DNA methylation is a common epigenetics signal that inhibits gene transcription, histone deacetylation similarly represses transcription but can be both epigenetics and non-epigenetics phenomena. The objective of this application is to advance the basic understanding of two key enzymes responsible for deacetylation and methylation, SIRT1 and DNMT1, and to transfer the knowledge from basic research findings of SIRT1/DNMT1 to clinical and patient oriented research. The project consists of three highly interactive and interdependent aims.
Aim 1 will test the hypothesis that SIRT1 regulates the activities and functions of DNMT1. The proposed work has potential to reveal that DNA methylation is tightly linked to other epigenetic signals, particularly histone deacetylation. Also, these studies may uncover an alternative, novel mechanism by which SIRT1 regulates epigenetic changes beyond the deacetylation of histones.
Aim 2 will focus on a systematic analysis of methylation status in DNMT1-regulated cancer-related genes, in the presence and absence of SIRT1. The results from this aim can lead to a better understanding of how key epigenetic regulators contribute to the pathogenesis and progression of cancer.
Aim 3 will test the hypothesis that SIRT1 and DNMT1 play a role in the growth control of established lung cancers. The efficacy of SIRT1 and DNMT1 inhibitors as potential anti- cancer drugs will be analyzed. The work in this last aim is translational and has the ability to suggest novel treatment strategies that can be proposed in future clinical trials. Although the common theme of rigorous SIRT1 and DNMT1 analysis resonates in all aims, different yet complementary sets of questions are raised in each aim with the ultimate goal of thoroughly understanding the functions and clinical relevance of SIRT1/DNMT1 and eventually applying that knowledge into potential diagnostic and therapeutic approaches for the treatment of cancer. Together, this project will help advance the cure of cancer through basic and translational research by utilizing laboratory-based science, cancer patients, and related networks.
The proposed project has potential to improve public health in several ways. First, the proposed work to study SIRT1 and DNMT1 has the potential to reveal novel etiological and pathogenesis pathways for some cancers. SIRT1 has oncogenic properties but, paradoxically, can act as a tumor suppressor. Inactivation of DNMT1 during embryogenesis causes tumors in adult mice, and overexpression of DNMT1 transforms cells. Second, the proposed studies potentially can lead to better prevention and diagnosis of cancer. SIRT1 may act as a potent regulator of aging-associated pathologies, including several types of cancer. Studies in this application may lead to prognostic and predictive information for cancer and help develop therapeutics that will extend aging and reduce malignancy. Finally, the proposed work may contribute to better treatments and cure of cancer. Histone deacetylases and DNA methyltransferases are potentially good targets for anti-cancer therapy. Our work to elucidate the efficacy of SIRT1 and DNMT1 inhibitors as potential anti-cancer drugs fits well with the ultimate goal to help alleviate human suffering from cancer.
|Villagra, A; Sahakian, E; Seto, E (2016) Preparation and Biochemical Analysis of Classical Histone Deacetylases. Methods Enzymol 573:161-81|
|Li, Yixuan; Seto, Edward (2016) HDACs and HDAC Inhibitors in Cancer Development and Therapy. Cold Spring Harb Perspect Med 6:|
|Radhakrishnan, Rangasudhagar; Li, Yixuan; Xiang, Shengyan et al. (2015) Histone deacetylase 10 regulates DNA mismatch repair and may involve the deacetylation of MutS homolog 2. J Biol Chem 290:22795-804|
|Sun, Lidong; Kokura, Kenji; Izumi, Victoria et al. (2015) MPP8 and SIRT1 crosstalk in E-cadherin gene silencing and epithelial-mesenchymal transition. EMBO Rep 16:689-99|
|Peng, Lirong; Yuan, Zhigang; Li, Yixuan et al. (2015) Ubiquitinated sirtuin 1 (SIRT1) function is modulated during DNA damage-induced cell death and survival. J Biol Chem 290:8904-12|
|Guan, D; Lim, J H; Peng, L et al. (2014) Deacetylation of the tumor suppressor protein PML regulates hydrogen peroxide-induced cell death. Cell Death Dis 5:e1340|
|Villagra, A; Sotomayor, E M; Seto, E (2010) Histone deacetylases and the immunological network: implications in cancer and inflammation. Oncogene 29:157-73|