Epigenetic regulation of epithelial-mesenchymal transition

Abstract

Epithelial-mesenchymal transition (EMT) is an essential process for morphogenesis and organ development which reversibly enables polarized epithelial cells to lose their epithelial characteristics and to acquire mesenchymal properties. It is now evident that the aberrant activation of EMT is also a critical mechanism to endow epithelial cancer cells with migratory and invasive capabilities associated with metastatic competence. This dedifferentiation program is mediated by a small cohort of pleiotropic transcription factors which orchestrate a complex array of epigenetic mechanisms for the wide-spread changes in gene expression. Here, we review major epigenetic mechanisms with an emphasis on histone modifications and discuss their implications in EMT and tumor progression. We also highlight mechanisms underlying transcription regulation concerted by various chromatin-modifying proteins and EMT-inducing transcription factors at different molecular layers. Owing to the reversible nature of epigenetic modifications, a thorough understanding of their functions in EMT will not only provide new insights into our knowledge of cancer progression and metastasis, but also facilitate the development of diagnostic and therapeutic strategies for human malignancy.

Keywords: Epigenetics; Epithelial–mesenchymal transition; Histone modifications; Transcription regulation; Tumor progression.

Fig. 1

Coordinated transcription regulations mediated by different EMT-TFs and chromatin-modifying proteins. a ZEB1/2 recruits CtBP co-repressor complex, in which HDAC1/2 and LSD1 remove histone acetylation and H3K4 methylation, respectively, whereas G9a/GLP introduces H3K9 methylation. b H3K9 methylation marks are recognized by HP1 proteins which further recruit DNMTs for promoter CpG methylation. c ZEB1 and SNAI1 recruit multiple H3K9 HMTases to target promoters, while the resulting methylation and G9a/GLP self-methylation could target MPP8 for methyl-H3K9 binding. MPP8 protein stability is dynamically regulated by PCAF- and SIRT1-catalyzed MPP8–K439 acetylation and deacetylation. d G9a/GLP also methylates DNMT3A, while the resulting K47 methylation facilitates DNMT3A recruitment by MPP8. e SNAI1 recruits multiple histone-modifying enzymes to remove permissive histone acetylation and H3K4 methylation to introduce repressive H3K9 methylation and H3K27 methylations. f DNMTs are further recruited by PRC2 and HP1 proteins to catalyze promoter CpG methylation. PRC1 is also recruited by binding to methyl-H3K27 marks on the promoter. g On epithelial gene promoters, TWIST1 recruits NuRD complex, SET8, and PRC2 for histone deacetylation, H4K20 methylation, and H3K27 methylation, respectively. It also recruits PRC1 directly and indirectly to introduce H2AK119 mono-ubiquitination. h On mesenchymal gene promoters, SET8-catalyzed H4K20 methylation serves as transcription activation mark (N-cadherin promoter). TWIST1 also forms a protein complex with TIP60/NuA4 which acetylates histone H4 and TWIST1. The acetylated lysines are recognized by BRD4 which recruits P-TEFb and super elongation complex to facilitate transcription (WNT5a promoter)