Research Interests:DNA methylation and epigenetics in cancer and normal cells Epigenetic regulation of androgen receptor signaling Role of folate metabolism in prostate cancer genomic and epigenomic stability
About Dominic Smiraglia
Dominic J. Smiraglia, PhD, joined the Roswell Park Comprehensive Cancer Center faculty in 2003 as an Assistant Member in the Department of Cancer Genetics.
Dr. Smiraglia comes to Roswell Park from the Division of Human Cancer Genetics at the Ohio State University (OSU), where he served as a Postdoctoral Fellow and as a Research Scientist. He earned his doctoral degree in the Department of Cell and Molecular Biology in 1997 from Roswell Park's Graduate Division and completed postdoctoral training in the Department of Molecular Virology, Immunology and Medical Genetics at OSU.
Dr. Smiraglia is a member of The DNA Methylation Society, The American Association for Cancer Research, and the Society for Basic Urological Research. He has authored or co-authored more than 50 journal publications and book chapters. He is an ad hoc reviewer for numerous journals including the Journal of Medical Genetics, Cancer Research, Blood, Oncogene and Oncology.
Roswell Park Comprehensive Cancer Center
- Associate Professor of Oncology
- Department of Cell Stress Biology
- Director of Graduate Studies, Cancer Genetics, Genomics and Development PhD Program
Education and Training:
- BA - State University of New York at Buffalo
- 1997 - PhD - Roswell Park Comprehensive Cancer Center, Buffalo, NY
- The Ohio State University, Department of Molecular Virology, Immunology, and Medical Genetics, Division of Human Cancer Genetics
- The DNA Methylation Society
- The American Association for Cancer Research
- Society for Basic Urological Research
The Smiraglia lab has two major themes over-arching their research program. The first is the idea that epigenetic modifications provide an exceptional route for cancer cell ‘evolution’ as cancers progress to advanced phenotypes. The second is the idea that epigenetic regulation is the means by which the genome can be responsive to the environment. These themes overlap in the sense that the environmental challenges to cancer cells change during tumor progression as they are required to adapt to metabolic pressures, such as hypoxia, inflammatory response, and stress on nucleotide pools. In the case of a hormone responsive tumor like prostate cancer, the environmental changes also include changes in hormonal stimulation and nuclear receptor action. Such environmental stresses are key to providing the selective pressures that are required to drive ‘evolution’ of cancers cells, making them adept at progressing to more advanced phenotypes.
A major direction for the lab has been the study of epigenetic changes in the advanced phenotypes of prostate cancer including castration recurrent and metastatic prostate cancer. These efforts have identified unique DNA methylation events in specific prostate cancer phenotypes and demonstrated the early onset of initial DNA methylation changes in the course of disease progression. In addition, the lab has continued to study DNA methylation patterns in normal tissues and found that neural tissues have distinctly different CpG island methylation patterns than non-neural1.
A major recent focus for the lab has been to study how folate metabolism impacts genome stability and epigenetic stability in prostate cancer. These studies take into consideration the uniquely high level of polyamine biosynthesis in prostate cells, and the stress that places on the methionine cycle and one-carbon metabolic pathways. Dietary intake of folate is essential to all three pathways. The Smiraglia lab has found that the high polyamine production in prostate cells makes them more sensitive to low levels of folate2.
Long term growth of prostate cells in low folate conditions led to changes in cell phenotype including increased proliferation rate in normal folate conditions, reduced sensitivity to low folate, and more anchorage independent colony formation3. Changes in cellular phenotype coincided with increased DNA damage, altered dTTP and dUTP pools, and altered S-adenosyl methionine (SAM) pools. Both nucleotide pool and SAM pool distortion changed over time as the cells adapted to low folate conditions. SAM pools donate the methyl group for DNA methylation reactions and their disruption led to increased CpG island hypermethylation. Furthermore, since SAM pools also donate methyl groups for protein methylation, global levels of methylated histones were also found to be altered with increased levels of H3K9 and –K36 methylation. Thus, long term growth in low folate conditions altered both genetic and epigenetic stability4. Notably, “low folate” in these experiments was only low for prostate cells, as colon cancer cells grown in the same condition were unaffected.
These folate studies have recently been taken into an in vivo model of prostate cancer. Using the TRAMP mouse model, recent work in the Smiraglia lab has found that manipulation of dietary folate status can significantly impact the course of disease progression. Dietary supplementation of folate significantly reduced the level of aberrant CpG island methylation in prostate tumors and slightly reduced the severity of disease. Dietary folate deficiency, however, dramatically blocked progression of the disease by blocking proliferation of prostate cancer cells. Current efforts are underway to explore the metabolic responses to dietary folate restriction in prostate tumor cells in terms of polyamine biosynthesis and other aspects of the methionine cycle and how they affect SAM pools and the ability of cells to maintain sufficient epigenetic regulation of the genome.
1The use of various DNA methylation scanning approaches to identify frequent targets of CpG island methylation in cancers.
2Study of DNA methylation in primary and androgen-independent human prostate cancer.
3Study of mouse models of prostate cancer to identify methylation events relating to the primary, metastatic and androgen-independent phenotypes.
4Study of folate and one-carbon metabolism and its impact on prostate cancer and epigenetics.
- Campbell MJ and Smiraglia DJ. Epigenetic contributions to the cancer transcriptome. Pathobiology of Human Disease: A Dynamic Encyclopedia of Disease Mechanisms. Linda M. McManus and Richard N. Mitchell (Editors). 2014. 367-380. ISBN 9780123864574. doi:/10.1016/B978-0-12-386456-7.01903-1.
- Bistulfi G, Diegelman P, Foster BA, Kramer DL, Porter CW, Smiraglia DJ. Polyamine biosynthesis impacts cellular folate requirements necessary to maintain S-adenosylmethionine and nucleotide pools. FASEB J. 2009 Sep;23(9):2888-97. doi: 10.1096/fj.09-130708. Epub 2009 May 5. PMID: 19417083; PMCID: PMC2735368.
- Bistulfi G, Vandette E, Matsui S, Smiraglia DJ. Mild folate deficiency induces genetic and epigenetic instability and phenotype changes in prostate cancer cells. BMC Biol. 2010 Jan 21;8:6. doi: 10.1186/1741-7007-8-6. PMID: 20092614; PMCID: PMC2845099.
- Bistulfi G, Foster BA, Karasik E, Gillard B, Miecznikowski J, Dhiman VK, Smiraglia DJ. Dietary folate deficiency blocks prostate cancer progression in the TRAMP model. Cancer Prev Res (Phila). 2011 Nov;4(11):1825-34. doi: 10.1158/1940-6207.CAPR-11-0140. Epub 2011 Aug 11. PMID: 21836022; PMCID: PMC3208799.
- Doig CL, Singh PK, Dhiman VK, Thorne JL, Battaglia S, Sobolewski M, Maguire O, O'Neill LP, Turner BM, McCabe CJ, Smiraglia DJ, Campbell MJ. Recruitment of NCOR1 to VDR target genes is enhanced in prostate cancer cells and associates with altered DNA methylation patterns. Carcinogenesis. 2013 Feb;34(2):248-56. doi: 10.1093/carcin/bgs331. Epub 2012 Oct 20. PMID: 23087083; PMCID: PMC3564435.
- Smiraglia DJ, Kulawiec M, Bistulfi GL, Gupta SG, Singh KK. A novel role for mitochondria in regulating epigenetic modification in the nucleus. Cancer Biol Ther. 2008 Aug;7(8):1182-90. doi: 10.4161/cbt.7.8.6215. Epub 2008 Aug 1. PMID: 18458531; PMCID: PMC2639623.
- Smiraglia DJ, Rush LJ, Frühwald M, Dai Z, Held WA, Costello JF, Lang JC, Eng C, Li B, Wright FA, Caligiuri MA, Plass C. Excessive CpG island hypermethylation in cancer cell lines versus primary human malignancies. Hum Mol Genet 10(13):1413-1419. doi:/10.1093/hmg/10.13.1413