Epigenetic alterations contribute to all stages of tumor progression and it is well recognized that aberrant DNA methylation and histone hypoacetylation of growth control genes and tumor suppressor genes directly contribute to malignancy. Because epigenetic changes are reversible, these alterations represent attractive targets for promising new anticancer agents and this property has been exploited recently for new therapies. While recent progress has lead to the FDA approval of the first two """"""""epigenetic therapies"""""""" the mechanistic basis for their efficacy is poorly understood. This proposal will explore entirely new links between a relatively unexplored class of deacetylases (the sirtuins) and proteins that bind to methylated DNA (methyl-CpG binding proteins) in gene silencing. These advances could help explain why some solid tumors are refractory to the current epigenetic therapies and provide a more complete mechanism by which tumor suppressor genes (TSGs) become heritably silenced. Elucidating the molecular basis for this epigenetic silencing of growth control genes and TSGs is important for identifying novel anticancer therapies and we propose to do the following:
Specific Aim 1 - Determine the role of methyl-CpG binding proteins in targeting SIRT1 to endogenous hypermethylated gene promoters.
Specific Aim 2 - Determine the contribution of methyl-CpG binding proteins and SIRT1 in regulating chromatin structure at silenced growth control and tumor suppressor genes.
Specific Aim 3 - Determine the functional significance of MeCP2 acetylation and deacetylation by SIRT1.

Public Health Relevance

Because multiple HDAC inhibitors are in various phases of clinical trials, it is important to understand how deacetylases contribute to tumorigenesis, and we have identified a novel role for the sirtuin family of deacetylases in tumor suppressor gene silencing.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Okano, Paul
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Louisiana State University Hsc Shreveport
Schools of Medicine
United States
Zip Code
Molehin, Deborah; Castro-Piedras, Isabel; Sharma, Monica et al. (2018) Aromatase Acetylation Patterns and Altered Activity in Response to Sirtuin Inhibition. Mol Cancer Res 16:1530-1542
Sharma, Monica; Castro-Piedras, Isabel; Simmons Jr, Glenn E et al. (2018) Dishevelled: A masterful conductor of complex Wnt signals. Cell Signal 47:52-64
Castro-Piedras, Isabel; Sharma, Monica; den Bakker, Meghan et al. (2018) DVL1 and DVL3 differentially localize to CYP19A1 promoters and regulate aromatase mRNA in breast cancer cells. Oncotarget 9:35639-35654
Pandey, Somnath; Pruitt, Kevin (2017) Functional assessment of MeCP2 in Rett syndrome and cancers of breast, colon, and prostate. Biochem Cell Biol 95:368-378
Dykes, Samantha S; Gray, Alana L; Coleman, David T et al. (2016) The Arf-like GTPase Arl8b is essential for three-dimensional invasive growth of prostate cancer in vitro and xenograft formation and growth in vivo. Oncotarget 7:31037-52
Manna, Pulak R; Stetson, Cloyce L; Slominski, Andrzej T et al. (2016) Role of the steroidogenic acute regulatory protein in health and disease. Endocrine 51:7-21
Saxena, M; Dykes, S S; Malyarchuk, S et al. (2015) The sirtuins promote Dishevelled-1 scaffolding of TIAM1, Rac activation and cell migration. Oncogene 34:188-98
Pandey, Somnath; Simmons Jr, Glenn E; Malyarchuk, Svitlana et al. (2015) A novel MeCP2 acetylation site regulates interaction with ATRX and HDAC1. Genes Cancer 6:408-21
Manna, Pulak R; Stetson, Cloyce L; Daugherty, Carol et al. (2015) Up-regulation of steroid biosynthesis by retinoid signaling: Implications for aging. Mech Ageing Dev 150:74-82
Manna, Pulak R; Sennoune, Souad R; Martinez-Zaguilan, Raul et al. (2015) Regulation of retinoid mediated cholesterol efflux involves liver X receptor activation in mouse macrophages. Biochem Biophys Res Commun 464:312-7

Showing the most recent 10 out of 14 publications