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.
Highlights
Cancer is characterized by pervasive epigenetic alterations with enhancer dysfunction orchestrating the aberrant cancer transcriptional programs and transcriptional dependencies
These results revealed that the conserved cancer-cell intrinsic Colorectal cancer (CRC)-enhancerome, shared by all patient-derived organoids (PDOs) and independent of patient-topatient tumor molecular diversity, is largely under the regulatory control of YAP/TAZ, suggesting that these transcriptional activators serve as central players in the epigenetic deregulation of CRC
In our study, the epigenetic landscape of human CRC unveils the existence of an aberrant pan-cancer core of enhancers regulated by the transcriptional coactivators YAP/TAZ and active in more than 20 types of human malignancies
Summary
PDO library as a model of human CRC heterogeneity. With De novo chromatin state discovery in human CRC. The high expression of EREG in PDOs was regulated by two separate enhancers located more than 200Kb downstream of the gene and occupied by TAZ and the active histone marks H3K4me[1], H3K27ac, and H3K4me[3] (Supplementary Fig. 5d) Another gene of the TAZ-driven CRC enhancerome is the Forkhead box Q1 (FOXQ1) member of the forkhead transcription factor family, which is involved in CRC tumorigenicity and growth[27] with no previously reported role as a YAP/TAZ downstream target gene. In situ hybridization in primary healthy and tumor colon tissues confirmed that FOXQ1 gene expression is restricted to the CRC sections that express YAP in the nucleus (Supplementary Fig. 5f) Taken together, these results revealed that the conserved cancer-cell intrinsic CRC-enhancerome, shared by all PDOs and independent of patient-topatient tumor molecular diversity, is largely under the regulatory control of YAP/TAZ, suggesting that these transcriptional activators serve as central players in the epigenetic deregulation of CRC. The role of YAP/TAZ as regulators of the conserved enhancerome of human CRC nicely parallels functional evidence in vivo, in mouse models, and in tumor organoids bearing YAP/
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