Abstract
Tumor metastasis is the major cause of mortality and morbidity in most solid cancers. A growing body of evidence suggests that the epithelial-to-mesenchymal transition (EMT) plays a central role during tumor metastasis and frequently imparts a stem cell-like phenotype and therapeutic resistance to tumor cells. The induction of EMT is accompanied by a dynamic reprogramming of the epigenome involving changes in DNA methylation and several post-translational histone modifications. These changes in turn promote the expression of mesenchymal genes or repress those associated with an epithelial phenotype. Importantly, in order for metastatic colonization and the formation of macrometastases to occur, tumor cells frequently undergo a reversal of EMT referred to as the mesenchymal-to-epithelial transition (MET). Thus, a high degree of epigenetic plasticity is required in order to induce and reverse EMT during tumor progression. In this review, we describe various epigenetic regulatory mechanisms employed by tumor cells during EMT and elaborate on the importance of the histone code in controlling both the expression and activity of EMT-associated transcription factors. We propose that a more thorough understanding of the epigenetic mechanisms controlling EMT may provide new opportunities which may be harnessed for improved and individualized cancer therapy based on defined molecular mechanisms.
Highlights
Metastatic disease accounts for more than 90% of deaths in patients with solid tumors [1]
Our understanding of metastasis has been greatly improved by the recognition that cancer cells can acquire the ability to accomplish several steps of the metastatic process at once through the engagement of a latent cellular program, the EpithelialMesenchymal Transition (EMT) [3,4]
Recent research points to the necessity of the reversal of EMT by means of a Mesenchymal-Epithelial Transition (MET) at the metastatic site to enable the outgrowth of disseminated tumor cells (DTC) into macroscopic metastases [10], supported by earlier work pointing to the importance of mesenchymal-to-epithelial transition (MET) in the metastatic cascade [11]
Summary
Metastatic disease accounts for more than 90% of deaths in patients with solid tumors [1]. Recent research points to the necessity of the reversal of EMT by means of a Mesenchymal-Epithelial Transition (MET) at the metastatic site to enable the outgrowth of disseminated tumor cells (DTC) into macroscopic metastases [10], supported by earlier work pointing to the importance of MET in the metastatic cascade [11] These experimental studies are supported by the clinicopathological observation that most metastases arising from carcinomas display an epithelial phenotype mimicking the differentiation patterns found in the cognate primary tumor site of a given tumor [12]. These seemingly opposing observations may be reconciled by comprehending EMT as a highly dynamic and reversible process In this scenario, the most aggressive tumor cells would be predicted to be those displaying a high degree of cellular plasticity or a mixed phenotype integrating epithelial and mesenchymal characteristics. Emphasis is laid primarily on histone modifications largely due to their amenability to intervention in possible future therapies to prevent metastasis or metastatic relapse
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