Polyamine flux suppresses histone lysine demethylases and enhances ID1 expression in cancer stem cells.
Keisuke TamariMasamitsu KonnoAyumu AsaiJun KosekiKazuhiko HayashiKoichi KawamotoNoriyuki MuraiSenya MatsufujiFumiaki IsohashiTaroh SatohNoriko GotoShinji TanakaYuichiro DokiMasaki MoriKazuhiko OgawaHideshi IshiiPublished in: Cell death discovery (2018)
Cancer stem cells (CSCs) exhibit tumorigenic potential and can generate resistance to chemotherapy and radiotherapy. A labeled ornithine decarboxylase (ODC, a rate-limiting enzyme involved in polyamine [PA] biosynthesis) degradation motif (degron) system allows visualization of a fraction of CSC-like cells in heterogeneous tumor populations. A labeled ODC degradation motif system allowed visualization of a fraction of CSC-like cells in heterogeneous tumor populations. Using this system, analysis of polyamine flux indicated that polyamine metabolism is active in CSCs. The results showed that intracellular polyamines inhibited the activity of histone lysine 4 demethylase enzymes, including lysine-specific demethylase-1 (LSD1). Chromatin immunoprecipitation with Pol II antibody followed by massively parallel DNA sequencing, revealed the global enrichment of Pol II in transcription start sites in CSCs. Increase of polyamines within cells resulted in an enhancement of ID1 gene expression. The results of this study reveal details of metabolic pathways that drive epigenetic control of cancer cell stemness and determine effective therapeutic targets in CSCs.
Keyphrases
- cancer stem cells
- gene expression
- dna methylation
- genome wide
- single cell
- induced apoptosis
- locally advanced
- transcription factor
- pet imaging
- signaling pathway
- poor prognosis
- early stage
- amino acid
- cell cycle arrest
- circulating tumor
- rectal cancer
- single molecule
- cell death
- cell free
- squamous cell carcinoma
- stem cells
- radiation induced
- binding protein
- epithelial mesenchymal transition
- endoplasmic reticulum stress
- genetic diversity
- cell proliferation
- cell wall
- human health
- pi k akt
- high throughput sequencing
- climate change
- nucleic acid
- circulating tumor cells