Epigenomic landscape of human colorectal cancer unveils an aberrant core of pan-cancer enhancers orchestrated by YAP/TAZ

Claudio Tripodo, Massimiliano Pagani, Giulia Della Chiara, Nicola Zucchini, Raoul Jean Pierre Bonnal, Marco De Simone, Andrea Cassingena, Luca Azzolin, Luca Gianotti, Valeria Ranzani, Mattia Forcato, Francesca Zanconato, Federica Pisati, Giuseppe Testa, Maria Lucia Sarnicola, Jimmy Caroli, Oriana Romano, Nicolò Maria Mariani, Lorenzo Drufuca, Grazisa RossettiGiulia Moreni, Francesco Panariello, Nicolò Maria Mariani, Federica Gervasoni, Tanya Fabbris, Ramona Bason, Ivan Ferrari, Claudia D’Oria, Chiara Godano, Giulia Moreni, Claudio Tripodo, Michelangelo Cordenonsi, Federica Pisati, Paola Gruarin, Andrea Pisani Ceretti, Silvio Bicciato, Enrico Opocher, Stefano Piccolo, Salvatore Siena, Alberto Bardelli, Giuseppe Macino, Andrea Sartore-Bianchi, Michaela Fakiola

Research output: Contribution to journalArticlepeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)2340-
Number of pages18
JournalNature Communications
Volume12
Publication statusPublished - 2021

All Science Journal Classification (ASJC) codes

  • General Chemistry
  • General Biochemistry,Genetics and Molecular Biology
  • General Physics and Astronomy

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