期刊
NATURE COMMUNICATIONS
卷 12, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-22544-y
关键词
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资金
- Italian Ministry of Education, University and Research (MIUR)
- National Council of Research of Italy (CNR)
- Fondazione AIRC [18575, 22759]
- European Research Council (ERC) CoG grant [617978]
- European Research Council (ERC) [670126]
- Fondazione Romeo ed Enrica Invernizzi
- University of Milan
- Fondazione Umberto Veronesi
- European Research Council (ERC) [670126, 617978] Funding Source: European Research Council (ERC)
This study epigenetically characterized human colorectal cancer and identified a tumor-specific deregulated enhancerome that is intrinsic to cancer cells. The research also revealed the key role of the transcriptional coactivators YAP/TAZ in regulating the gained enhancers in CRC and demonstrated their potential therapeutic implications.
Cancer is characterized by pervasive epigenetic alterations with enhancer dysfunction orchestrating the aberrant cancer transcriptional programs and transcriptional dependencies. Here, we epigenetically characterize human colorectal cancer (CRC) using de novo chromatin state discovery on a library of different patient-derived organoids. By exploring this resource, we unveil a tumor-specific deregulated enhancerome that is cancer cell-intrinsic and independent of interpatient heterogeneity. We show that the transcriptional coactivators YAP/TAZ act as key regulators of the conserved CRC gained enhancers. The same YAP/TAZ-bound enhancers display active chromatin profiles across diverse human tumors, highlighting a pan-cancer epigenetic rewiring which at single-cell level distinguishes malignant from normal cell populations. YAP/TAZ inhibition in established tumor organoids causes extensive cell death unveiling their essential role in tumor maintenance. This work indicates a common layer of YAP/TAZ-fueled enhancer reprogramming that is key for the cancer cell state and can be exploited for the development of improved therapeutic avenues.
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