Targeting bivalency de-represses Indian Hedgehog and inhibits self-renewal of colorectal cancer-initiating cells
| Autor: | Dalia Barsyte-Lovejoy, Bradly G. Wouters, Jian Jin, Jennifer Haynes, Antonija Kreso, Aaron Pollett, Anqi Ma, Catherine A. O’Brien, Cherry Leung, Evelyne Lima-Fernandes, Daniel D. De Carvalho, Genna M. Luciani, Yadong Wang, Shili Duan, Mathieu Lupien, Constanze Zeller, Tiago Medina, Alex Murison, Cheryl H. Arrowsmith |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Indian hedgehog Pyridones Science General Physics and Astronomy Mice SCID macromolecular substances 02 engineering and technology Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Mice Inbred NOD Differentiation therapy Animals Humans Enhancer of Zeste Homolog 2 Protein Hedgehog Proteins Epigenetics Cell Self Renewal lcsh:Science Cell Proliferation Epigenomics Multidisciplinary biology EZH2 Cell Differentiation General Chemistry 021001 nanoscience & nanotechnology biology.organism_classification Cell biology 030104 developmental biology Histone Neoplastic Stem Cells biology.protein H3K4me3 Female lcsh:Q Fluorouracil Colorectal Neoplasms 0210 nano-technology Bivalent chromatin |
| Zdroj: | Nature Communications, Vol 10, Iss 1, Pp 1-14 (2019) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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