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Enhancer reprogramming in tumor progression: a new route towards cancer cell plasticity

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Abstract

Cancer heterogeneity arises during tumor progression as a consequence of genetic insults, environmental cues, and reversible changes in the epigenetic state, favoring tumor cell plasticity. The role of enhancer reprogramming is emerging as a relevant field in cancer biology as it supports adaptation of cancer cells to those environmental changes encountered during tumor progression and metastasis seeding. In this review, we describe the cancer-related alterations that drive oncogenic enhancer activity, leading to dysregulated transcriptional programs. We discuss the molecular mechanisms of both cis- and trans-factors in overriding the regulatory circuits that maintain cell-type specificity and imposing an alternative, de-regulated enhancer activity in cancer cells. We further comment on the increasing evidence which implicates stress response and aging-signaling pathways in the enhancer landscape reprogramming during tumorigenesis. Finally, we focus on the potential therapeutic implications of these enhancer-mediated subverted transcriptional programs, putting particular emphasis on the lack of information regarding tumor progression and the metastatic outgrowth, which still remain the major cause of mortality related to cancer.

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Acknowledgements

We wish to express our appreciation to Center of Integrative Biology (CIBIO) of the University of Trento for granting a postdoctoral fellowship to Luca Fagnocchi. The authors also wish to acknowledge the Fondazione AIRC for granting a postdoctoral fellowship to Vittoria Poli (AIRC-M ID 21158). Work in Zippo group was supported by grants from the Italian Ministry of Health (GR-2011-02351172), and CARIPLO foundation (2014-0915).

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Authors and Affiliations

  1. Laboratory of Chromatin Biology and Epigenetics, Center for Integrative Biology (CIBIO), University of Trento, 38123, Trento, Italy

    Luca Fagnocchi, Vittoria Poli & Alessio Zippo

  2. Department of Epigenetics, Fondazione Istituto Nazionale di Genetica Molecolare “Romeo ed Enrica Invernizzi”, Via F. Sforza 35, 20122, Milan, Italy

    Alessio Zippo

  3. Division of Pathology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy

    Alessio Zippo

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  1. Luca Fagnocchi
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  2. Vittoria Poli
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  3. Alessio Zippo
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Correspondence to Luca Fagnocchi or Alessio Zippo.

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Fagnocchi, L., Poli, V. & Zippo, A. Enhancer reprogramming in tumor progression: a new route towards cancer cell plasticity. Cell. Mol. Life Sci. 75, 2537–2555 (2018). https://doi.org/10.1007/s00018-018-2820-1

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  • DOI: https://doi.org/10.1007/s00018-018-2820-1

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