TY - JOUR
T1 - Polyamine flux suppresses histone lysine demethylases and enhances ID1 expression in cancer stem cells
AU - Tamari, Keisuke
AU - Konno, Masamitsu
AU - Asai, Ayumu
AU - Koseki, Jun
AU - Hayashi, Kazuhiko
AU - Kawamoto, Koichi
AU - Murai, Noriyuki
AU - Matsufuji, Senya
AU - Isohashi, Fumiaki
AU - Satoh, Taroh
AU - Goto, Noriko
AU - Tanaka, Shinji
AU - Doki, Yuichiro
AU - Mori, Masaki
AU - Ogawa, Kazuhiko
AU - Ishii, Hideshi
N1 - Funding Information:
We thank laboratory staffs for their helpful discussion. This work received financial support partially from grants-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology (grant nos. 17H04282, 17K19698, 16K15615, and 15H057919) and Taiho Pharmaceutical Co., Ltd. (to J.K., M.M., and H.I.).
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41420-018-0117-7
DO - 10.1038/s41420-018-0117-7
M3 - Article
AN - SCOPUS:85070980489
SN - 2058-7716
VL - 4
JO - Cell Death Discovery
JF - Cell Death Discovery
IS - 1
M1 - 104
ER -
