Nature communications, 2019-03, Vol.10 (1), p.1436-14, Article 1436
- Lima-Fernandes, Evelyne
- Murison, Alex
- da Silva Medina, Tiago
- Wang, Yadong
- Ma, Anqi
- Leung, Cherry
- Luciani, Genna M.
- Haynes, Jennifer
- Pollett, Aaron
- Zeller, Constanze
- Duan, Shili
- Kreso, Antonija
- Barsyte-Lovejoy, Dalia
- Wouters, Bradly G.
- Jin, Jian
- Carvalho, Daniel D. De
- Lupien, Mathieu
- Arrowsmith, Cheryl H.
- O’Brien, Catherine A.
2019
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- Autor(en) / Beteiligte
- Lima-Fernandes, Evelyne
- Murison, Alex
- da Silva Medina, Tiago
- Wang, Yadong
- Ma, Anqi
- Leung, Cherry
- Luciani, Genna M.
- Haynes, Jennifer
- Pollett, Aaron
- Zeller, Constanze
- Duan, Shili
- Kreso, Antonija
- Barsyte-Lovejoy, Dalia
- Wouters, Bradly G.
- Jin, Jian
- Carvalho, Daniel D. De
- Lupien, Mathieu
- Arrowsmith, Cheryl H.
- O’Brien, Catherine A.
- Titel
- Targeting bivalency de-represses Indian Hedgehog and inhibits self-renewal of colorectal cancer-initiating cells
- Ist Teil von
- Nature communications, 2019-03, Vol.10 (1), p.1436-14, Article 1436
- Ort / Verlag
- London: Nature Publishing Group UK
- Erscheinungsjahr
- 2019
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- In embryonic stem cells, promoters of key lineage-specific differentiation genes are found in a bivalent state, having both activating H3K4me3 and repressive H3K27me3 histone marks, making them poised for transcription upon loss of H3K27me3. Whether cancer-initiating cells (C-ICs) have similar epigenetic mechanisms that prevent lineage commitment is unknown. Here we show that colorectal C-ICs (CC-ICs) are maintained in a stem-like state through a bivalent epigenetic mechanism. Disruption of the bivalent state through inhibition of the H3K27 methyltransferase EZH2, resulted in decreased self-renewal of patient-derived C-ICs. Epigenomic analyses revealed that the promoter of Indian Hedgehog ( IHH ), a canonical driver of normal colonocyte differentiation, exists in a bivalent chromatin state. Inhibition of EZH2 resulted in de-repression of IHH, decreased self-renewal, and increased sensitivity to chemotherapy in vivo. Our results reveal an epigenetic block to differentiation in CC-ICs and demonstrate the potential for epigenetic differentiation therapy of a solid tumour through EZH2 inhibition. The presence of bivalent epigenetic active and repressive histone marks control lineage-specific differentiation in embryonic stem cells. Here, the authors reveal that bivalent marks repress the differentiation gene IHH in colorectal cancer-initiating cells, and can be targeted by EZH2 inhibition
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2041-1723eISSN: 2041-1723DOI: 10.1038/s41467-019-09309-4Titel-ID: cdi_doaj_primary_oai_doaj_org_article_03a72eb189654119bb1c127366a2d06f
- Format
- –
- Schlagworte
- 13, 13/106, 13/31, 14, 14/1, 14/63, 38/77, 38/91, 42, 45, 45/15, 49, 631/208/176, 631/67/1504/1885, 631/67/71, 82/51, 82/80, 96, 96/44, Animals, Cancer, Cell Differentiation - drug effects, Cell Differentiation - genetics, Cell Proliferation - drug effects, Cell Self Renewal - drug effects, Cell self-renewal, Chemotherapy, Chromatin, Colorectal cancer, Colorectal carcinoma, Colorectal Neoplasms - metabolism, Colorectal Neoplasms - pathology, Differentiation, Disruption, Embryo cells, Enhancer of Zeste Homolog 2 Protein - metabolism, Epigenetics, Female, Fluorouracil - pharmacology, Hedgehog protein, Hedgehog Proteins - metabolism, Humanities and Social Sciences, Humans, Inhibition, Male, Methyltransferase, Mice, Inbred NOD, Mice, SCID, multidisciplinary, Neoplastic Stem Cells - drug effects, Neoplastic Stem Cells - metabolism, Neoplastic Stem Cells - pathology, Paraechinus micropus, Pyridones - pharmacology, Science, Science (multidisciplinary), Solid tumors, Stem cells, Transcription