|Department Affiliations||Oncology, Urology, Pharmacology, Medicine, Pathology, and Radiation Oncology|
|SOM Address||Suite 1100 Weinberg Building|
Bryon Lee 2001 – 2206
Our laboratory is dedicated to improving prostate cancer prevention and treatment via studies of the molecular pathogenesis of the disease. We have found that somatic inactivation of GSTP1, encoding a carcinogen-detoxification enzyme, by CpG island hypermethylation, likely initiates human prostatic carcinogenesis by increasing the vulnerability of prostate cells to genome damage mediated by electrophilic and oxidant carcinogens. GSTP1 is normally expressed in prostate basal epithelial cells, the stem cells for the prostatic epithelium, but not in columnar secretory epithelial cells. In proliferative inflammatory atrophy (PIA) lesions, the earliest precursors to prostatic intraepithelial neoplasia (PIN) and to prostate cancer, GSTP1 appears induced as part of a stress response associated with exposure to inflammatory oxidants. Loss of GSTP1 expression, attributable to GSTP1 CpG island hypermethylation, is characteristic of ~70% of PIN lesions and >90% of prostate cancers. Cancer cells devoid of GSTP1 accumulate more genome damage upon exposure to electrophilic carcinogens, such as those present in well-done or charred meats, or to oxidants.
Key research objectives under current scrutiny in the laboratory include: (i) elucidating the mechanism by which CpG island hypermethylation leads to GSTP1 gene silencing in prostate cancer cells, (ii) discovering the manner by which the GSTP1 CpG island accumulates abnormally methylated CpG dinucleotides, (iii) characterizing the phenotype of prostate cells deficient in GSTP1 activity, and (iv) exploring new avenues for prostate cancer prevention and treatment targeting DNA methyltransferases (DNMTs), 5-meC-binding domain proteins (MBDs), and carcinogen detoxification enzymes. Nakayama, M., Bennett, C.J., Hicks, J.L., Epstein, J.I., Platz, E.A., Nelson, W.G., and De Marzo, A.M. Hypermethylation of the human glutathione S-transferase-p gene (GSTP1) CpG island is present in a subset of proliferative inflammatory atrophy lesions but not in normal or hyperplastic epithelium of the prostate: a detailed study using laser-capture microdissection. Am J Pathol, 163: 923-933, 2003.
- Aryee, M.J., Liu, W., Engelmann, J.C., Nuhn, P., Gurel, M., Haffner, M.C., Esopi, D,. Irizarry, R.A., Getzenberg, R.H., Nelson, W.G., Luo, J., Xu, J., Isaacs, W.B., Bova, G.S., and Yegnasubramanian, S. DNA methylation alterations exhibit intraindividual stability and interindividual heterogeneity in prostate cancer metastases. Transl. Med. 5: 169ra10 (2013).
- Weier, C., Haffner, M.C., Mosbruger, T., Esopi, D.M., Hicks, J., Zheng, Q., Fedor, H., Isaacs, W.B., De Marzo, A.M., Nelson, W.G., and Yegnasubramanian, S. Nucleotide resolution analysis of TMPRSS2 and ERG rearrangements in prostate cancer.. Pathol. 230: 174-83 (2013).
- Haffner, M.C., Pellakuru, L.G., Ghosh, S., Lotan, T.L., Nelson, W.G., De Marzo, A.M., and Yegnasubramanian, S. Tight correlation of 5-hydroxymethylcytosine and Polycomb marks in health and disease.. Cell Cycle 12: 1835-1841 (2013).
- Haffner, M.C., Mosbruger, T., Esopi, D.M., Fedor, H., Heaphy, C.M., Walker, D.A., Adejola, N., Gürel, M., Hicks, J., Meeker, A.K., Halushka, M.K., Simons, J.W., Isaacs, W.B., De Marzo, A.M., Nelson, W.G., and Yegnasubramanian, S. Tracking the clonal origin of lethal prostate cancer.. Clin. Invest. 123: 4918-4922 (2013).*
- Wyhs, N., Walker, D., Giovinazzo, H., Yegnasubramanian, S., and Nelson, W.G. Time-resolved fluorescence resonance energy transfer assay for discovery of small-molecule inhibitors of methyl-CpG binding domain protein 2. . Biomol. Screen. 19: 1060-1069 (2014).