The overall objective of this renewal is to test the hypothesis that our novel polyamine analogue inhibitors of lysine specific demethylase 1 (LSD1), used alone or in combination with other agents targeting epigenetic silencing, will be more efficacious in re-activating aberrantly silenced genes in cancer cells than current strategies, thus having the potential to improve treatment of cancer. Aberrant epigenetic silencing of tumor suppressor genes is critically important in the initiation and progression of cancer. Histone modifications (acetylation, phosphorylation, and methylation) result in a combination of histone marks that act in concert with gene promoter CpG DNA methylation status to determine whether chromatin is in an open/actively transcribed, or closed/transcriptionally repressed conformation. Thus dysregulation of these processes can lead to aberrant silencing of genes. Several laboratories, including our own, have investigated means by which aberrant epigenetically silenced genes may be reactivated for therapeutic advantage. This approach is based on the fact that unlike gene mutations, epigenetic modifications are reversible. Histone modifications are a result of dynamic processes;a prime example is the balance of histone acetylation maintained by histone acetyltransferases and histone deacetylases. Recently a similar dynamic process has been demonstrated for histone methylation. The first histone lysine demethylase discovered, LSD1, an FAD-dependent oxidase, targets mono- and dimethyl-lysine 4 histone 3 (H3K4me1 &H3K4me2). Promoter region H3K4me2 is associated with transcriptionally active genes and is considered an activating mark. Therefore, demethylation by LSD1 may broadly repress gene expression. Emerging data associate LSD1 activity with abnormal gene silencing and thus LSD1 may be a target for therapeutic manipulation to facilitate the re-expression of aberrantly silenced genes. The catalytic domain of LSD1 is homologous to the FAD-dependent spermine oxidase (SMO). Our laboratory first cloned and characterized SMO and aided in the discovery of LSD1. Based on our expertise in polyamine catabolism, we hypothesized that polyamine analogues could inhibit LSD1 and reactivate epigenetically silenced genes. We have discovered specific polyamine analogues that are potent inhibitors of LSD1, leading to re-expression of aberrantly silenced genes important in tumorigenesis. Gene re-expression is subsequent to increased promoter chromatin activating marks and decreased repressive marks. Therefore, to assess the potential of LSD1 as a target for therapy, we will: 1) evaluate our new polyamine analogue inhibitors of LSD1 alone and in combination with inhibitors of histone deacetylases and/or DNA methyltransferases for their ability to re-express aberrantly silenced genes;2) evaluate the in vivo effectiveness of our LSD1 inhibitors alone and in combination with other agents targeting epigenetic modifications.
Aberrant silencing of genes is a major contributor to the development of cancer. LSD1 is an enzyme that contributes to aberrant gene silencing. Therefore, developing our inhibitors of LSD1 and understanding the molecular mechanisms by which they reactivate silenced genes will improve our ability to target aberrant gene silencing for the treatment of cancer.
|Chaturvedi, R; de Sablet, T; Asim, M et al. (2015) Increased Helicobacter pylori-associated gastric cancer risk in the Andean region of Colombia is mediated by spermine oxidase. Oncogene 34:3429-40|
|Zahedi, Kamyar; Barone, Sharon; Wang, Yang et al. (2014) Proximal tubule epithelial cell specific ablation of the spermidine/spermine N1-acetyltransferase gene reduces the severity of renal ischemia/reperfusion injury. PLoS One 9:e110161|
|Bhansali, Pravin; Hanigan, Christin L; Perera, Lalith et al. (2014) Synthesis and biological evaluation of largazole analogues with modified surface recognition cap groups. Eur J Med Chem 86:528-41|
|Chaturvedi, Rupesh; Asim, Mohammad; Piazuelo, M Blanca et al. (2014) Activation of EGFR and ERBB2 by Helicobacter pylori results in survival of gastric epithelial cells with DNA damage. Gastroenterology 146:1739-51.e14|
|Battaglia, Valentina; DeStefano Shields, Christina; Murray-Stewart, Tracy et al. (2014) Polyamine catabolism in carcinogenesis: potential targets for chemotherapy and chemoprevention. Amino Acids 46:511-9|
|Prusevich, Polina; Kalin, Jay H; Ming, Shonoi A et al. (2014) A selective phenelzine analogue inhibitor of histone demethylase LSD1. ACS Chem Biol 9:1284-93|
|Chaturvedi, Rupesh; Asim, Mohammad; Barry, Daniel P et al. (2014) Spermine oxidase is a regulator of macrophage host response to Helicobacter pylori: enhancement of antimicrobial nitric oxide generation by depletion of spermine. Amino Acids 46:531-42|
|Murray-Stewart, Tracy; Hanigan, Christin L; Woster, Patrick M et al. (2013) Histone deacetylase inhibition overcomes drug resistance through a miRNA-dependent mechanism. Mol Cancer Ther 12:2088-99|
|Nowotarski, Shannon L; Woster, Patrick M; Casero Jr, Robert A (2013) Polyamines and cancer: implications for chemotherapy and chemoprevention. Expert Rev Mol Med 15:e3|
|Casero Jr, Robert A (2013) Say what? The activity of the polyamine biosynthesis inhibitor difluoromethylornithine in chemoprevention is a result of reduced thymidine pools? Cancer Discov 3:975-7|
Showing the most recent 10 out of 105 publications