|Department Affiliations||Oncology, SOM; Environmental Health Sciences, SPH|
|SOM Address||Room 551 Cancer Research Building I|
Research in the Casero Laboratory is focused on the role of polyamines in cancer cell proliferation and ways to exploit their metabolism and function as antiproliferative and chemopreventive targets. Polyamines are naturally occurring polycationic alkylamines that are absolutely required for eukaryotic cell growth and differentiation. Their intracellular concentrations (millimolar) are maintained in a narrow range through the actions of a highly regulated and specific transport system and a rapidly responding metabolic pathway.
The first rate-limiting step in the production of polyamines is the decarboxylation of ornithine by the highly inducible and short-lived enzyme, ornithine decarboxylase (ODC). Increased ODC activity and new polyamine synthesis have frequently been associated with the neoplastic phenotype. The catabolism of the polyamines is controlled by the rate limiting enzyme spermidine/spermine N1-acetyltransferase (SSAT) that my laboratory has cloned and continues to study. This enzyme is highly controlled at the level of transcription, translation and is stabilized by the natural polyamines and antitumor polyamine analogues. We have also demonstrated that the phenotype-specific antitumor activity of specific polyamine analogues is associated with a superinduction of this enzyme in response to treatment.
Another enzyme cloned in my laboratory is the inducible FAD-dependent, spermine oxidase (SMOX) that is also a polyamine catabolic enzyme that produces H2O2 as one of its products. SMOX is induced by many inflammatory stimuli including bacterial infection and inflammatory cytokines. As an example, Helicobacter pylori, a causative agent of gastric cancer, highly induces SMOX resulting in sufficient H2O2 production to produce oxidative DNA damage. We have also demonstrated that SMOX is induced by a toxigenic strain of Bacteriodes fragilis, a bacteria that is associated with colon cancer. In an animal model of colon cancer induced by B. fragilis, the Casero lab demonstrated inhibiting SMOX significantly reduced tumor formation. Importantly, SMOX-produced H2O2 and subsequent DNA damage have been implicated in epigenetic changes that are common in the early stages of cancer development. Thus it appears that SMOX may be one of the molecular links between inflammation, DNA damage, epigenetic changes, and carcinogenesis and as such, represents a promising target for chemopreventive intervention. The lab is now engaged in an active program to identify well-tolerated agents that inhibit SMOX for use in chemoprevention strategies.
During the studies that lead to the discovery of SMOX, we also identified the sequence of a related FAD-dependent oxidase that was later identified as lysine specific demethylase 1 (LSD1). LSD1 is an important chromatin-remodeling enzyme that demethylates mono- and dimethyl lysine 4 of histone 3 (H3K4me1 & H3K4me2). As these histone marks are associated with active transcription, LSD1 has the ability to broadly repress gene transcription. LSD1 activity is involved with the inappropriate silencing of several tumor suppressor gene involved in the etiology and progression of cancer. As LSD1 is structurally and functionally homologous to SMOX, we hypothesized that certain polyamine analogues would inhibit LSD1 and lead to the re-expression of inappropriately silenced genes. We have now demonstrated that this is, in fact, the case and are pursuing this strategy to develop agents that may be useful in the treatment of neoplastic disease.
Consequently, polyamine metabolism and function, and related pathways present a target rich environment against which therapeutic and chemopreventive strategies may be developed.
Murray-Stewart, T., Sierra, J.C., Piazuelo, M.B., Mera, R.M., Chaturvedi, R., Bravo, L.E., Correa, P., Schneider, B.G., Wilson, K.T., and Casero, R.A. miR-124 methylation contributes to Helicobacter pylori-induced gastric carcinogenesis by preventing spermine oxidase regulation. Oncogene. In press, DOI: 10.1038/onc.2016.91 2016.
Luo H, Shenoy AK, Li X, Jin Y, Jin L, Cai Q, Tang M, Liu Y, Chen H, Reisman D, Wu L, Seto E, Qiu Y, Dou Y, Casero RA Jr, Lu J. MOF Acetylates the Histone Demethylase LSD1 to Suppress Epithelial-to-Mesenchymal Transition. Cell Rep. 2016 Jun 21;15(12):2665-78. doi: 10.1016/j.celrep.2016.05.050. Epub 2016 Jun 9. PMID:27292636
Murray-Stewart, T.R., Woster, P.M., and Casero, R.A. Targeting polyamine metabolism for cancer therapy and prevention. Biochemical J. In press, 2016. Zahnow, C.A., Topper, M., Stone, M., Murray-Stewart, T., Li, H., Baylin, S.B. & Casero, R.A., Jr. Inhibitors of DNA Methylation, Histone Deacetylation, and Histone Demethylation: A Perfect Combination for Cancer Therapy. Adv Cancer Res 130, 55-111, 2016.
Johnson, C.H., Dejea, C.M., Edler, D., Hoang, L.T., Santidrian, A.F., Felding, B.H., Ivanisevic, J., Cho, K., Wick, E.C., Hechenbleikner, E.M., Uritboonthai, W., Goetz, L., Casero, R.A., Pardoll, D.M., White, J.R., Patti, G.J., Sears, C., and Siuzdak, G. Metabolism links bacterial biofilms and colon carcinogenesis. Cell Metabolism. 21:891-897, 2015.
Chaturvedi, R., de Sablet, T., Asim, M., Blanca Piazuelo, M., Baryy, D.P., Verriere, T.G., Sierra, J.C., Hardbower, D.M., Degado, A.G., Schneider, B.G., Israel, D.A., Romero-Gallo, J., Nagy, T.A., Morgan, D.R., Murray-Stewart, T, Bravo, L.E., Peek, R.M., Fox, J.G., Woster, P.M., Casero, R.A., Correa, P., and Wilson, K.T. Increased Helicobacter pylori-associated gastric cancer risk in the Andean region of Colombia is mediated by spermine oxidase. Oncogene. 34:3429-3440, 2015.
Murray-Stewart, T., Woster, P.M., and Casero, R.A. The re-expression of the epigenetically silenced e-cadherin gene by a polyamine analogue lysine-specific demethylase-1 (LSD1) inhibitor in human acute myeloid leukemia cell lines.Amino Acids. 46:585-594, 2014.
Battaglia, V., Destefano Shields, C., Murray-Stewart, and Casero, R.A. Polyamine catabolism in carcinogenesis: potential targets for chemotherapy and chemoprevention. Amino Acids, 46:511-519, 2014.
Murray-Stewart, T., Hanigan, C.L., Woster, P.M., Marton, L.J., and Casero, R.A. Histone deacetylase inhibition overcomes drug resistance through a miRNA-dependent mechanism. mechanism. Molec. Cancer Ther., 12:2088-2099, 2013.
Schenk, T., Chen, W.C., Gollner, S., Howell, L., Jin, L., Hebestreit, K., Klein, h.-K., Popescu, A.C., Burnett, A., Mills, K., Casero, R., Marton, L., Woster, P., Minden, M.D., Dugas, M., Wang, J.C.Y., Dick, J.E., Muller-Tidow, C., Petrie, K., and Zelent, Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia. Nature Medicine, 18:605-611, 2012.
Goodwin, A.C., Wu, S., Huso, D.L., Wu, X., Destefano Shields, C.E., Hacker-Prietz, A., Rabizadeh, S., Sears, C.L., and Casero, R.A. Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis-induced colon tumorigenesis. Proc. Natl. Acad. Sci USA, 108(37):15354-9. 2011.
Casero, R. and Marton, L. Polyamine Metabolism and Function: A Target Rich Environment in the Battle Against Cancer and Other Hyperproliferative Diseases. Nature Rev. Drug Devel. 6:373-390, 2007.
Shi, Y., Lan, F., Matson, C., Mulligan, P., Whetstine, J.R., Cole, P.A., Casero, R.A., and Shi, Y. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119:941-953, 2004.