Abstract 4774: Polyamines are rich and induces epigenetic change by inhibition of LSD1 in cancer stem-like cells

Abstract

Abstract Cancer stem cells (CSC) are highly tumorigenic and resistant to chemotherapy and radiotherapy. We have previously reported that a small fraction of cancer cells with low proteasome activity had CSC-like properties. Ornithine decarboxylase (ODC) is an enzyme which converts ornithine to polyamines including putrescine, spermidine, and spermine. Proteasomal degradation of ODC is known to be ubiquitin-independent. The aim of this study was to explain how low proteasome activity gave CSC-like properties. Western blot showed high ODC protein level in CSC-like cells in cervical cancer and osteosarcoma cell lines, although ODC mRNA level is not high. These findings suggest that ODC protein level is high in CSC-like cells because ODC protein degradation is inactive. To investigate polyamine metabolism in CSC-like cells, we performed GC-MS analysis and found that putrescine, spermidine, and spermine were enriched in CSC-like cells. Furthermore, flux analysis showed conversion from ornithine to polyamines was more rapid in CSC-like cells. We performed a computational structure analysis and found that polyamines bind and inhibit demethylase site of LSD1 which is known to be a demethylase of histone H3K4 and a nuclear homolog of amine oxidases. Spermine was the strongest binding energy. An enzyme assay showed that LSD1 activity was dose-dependently inhibited by polyamines and spermine was the strong inhibitor. Finally, we analyzed performed ChIP sequencing analysis by using HeLa CSC-like cells and found that more global enrichment of H3K4me3 and less global enrichment of H3K4me1 than non-CSC-like cells. In conclusion, polyamines are rich in CSC, and be able to inhibit LSD1 activty and induce epigenetic alterations especially in H3K4 methylation in CSC. Citation Format: Keisuke Tamari, Hideshi Ishii, Masamitsu Konno, Naohiro Nishida, Jun Koseki, Koichi Kawamoto, Fumiaki Isohashi, Yuichiro Doki, Masaki Mori, Kazuhiko Ogawa. Polyamines are rich and induces epigenetic change by inhibition of LSD1 in cancer stem-like cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4774. doi:10.1158/1538-7445.AM2017-4774