Dominic Smiraglia

Research Overview:

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 stability³.  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.

The use of various DNA methylation scanning approaches to identify frequent targets of CpG island methylation in cancers.

Study of DNA methylation in primary and androgen-independent human prostate cancer.

Study of mouse models of prostate cancer to identify methylation events relating to the primary, metastatic and androgen-independent phenotypes.

Study of folate and one-carbon metabolism and its impact on prostate cancer and epigenetics.