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Annual Review of Cancer Biology

Volume 9, 2025

Genetic and Epigenetic Dysregulation of Transcriptional Enhancers in Cancer

  • Giovanni A. Botten1 and Jian Xu2
  • 1Department of Pathology and Laboratory Medicine, University of California, Los Angeles, California, USA; email: [email protected] 2Center of Excellence for Leukemia Studies, Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA; email: [email protected]
  • Vol. 9:79-97 (Volume publication date April 2025)
  • First published as a Review in Advance on October 30, 2024
  • Copyright © 2025 by the author(s).
    This work is licensed under a Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. See credit lines of images or other third-party material in this article for license information.

Abstract

Enhancers are noncoding DNA sequences responsible for orchestrating gene expression programs by interacting with transcription factors and chromatin regulators within complex genome structures. However, their fundamental functions can be disrupted by genetic and epigenetic alterations, leading to aberrant enhancer activation or rewiring that contributes to oncogenesis. Analyzing dysregulated enhancer landscapes reveals new subtype-defining genomic features, such as enhancer hijacking, and identifies disease-relevant transcriptional regulators as potential targets for developing enhancer-targeting therapeutic strategies. Here, we delve into evolving concepts and technologies for studying enhancers; discuss how genetic, epigenetic, and topological alterations disrupt enhancer regulation to promote oncogenic gene expression; and underscore the importance of understanding the regulatory principles governing enhancer function to guide therapeutic strategies. Furthermore, we highlight key challenges and emerging opportunities in targeting enhancers and their regulators to improve cancer classification, prognosis, and treatment.

Keyword(s): cancer therapy, enhancer hijacking, epigenetics, noncoding genome, structural variation, transcriptional enhancer
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2025-04-11
2025-06-13
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/content/journals/10.1146/annurev-cancerbio-060324-114306
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Genetic and Epigenetic Dysregulation of Transcriptional Enhancers in Cancer
Annual Review of Cancer Biology 9, 79 (2025); https://doi.org/10.1146/annurev-cancerbio-060324-114306
/content/journals/10.1146/annurev-cancerbio-060324-114306
/content/journals/10.1146/annurev-cancerbio-060324-114306
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