Epithelial to mesenchymal transition (EMT) is essential for driving plasticity during development, but is an unintentional behaviour of cells during cancer progression. The EMT-associated reprogramming of cells not only suggests that fundamental changes may occur to several regulatory networks but also that an intimate interplay exists between them. Disturbance of a controlled epithelial balance is triggered by altering several layers of regulation, including the transcriptional and translational machinery, expression of non-coding RNAs, alternative splicing and protein stability.

Regulatory networks defining EMT during cancer initiation and progression

Since the Von Hippel-Lindau (VHL) disease tumour suppressor gene VHL was identified in 1993 as the genetic basis for a rare disorder, it has proved to be of wide medical and scientific interest. VHL tumour suppressor protein (pVHL) plays a key part in cellular oxygen sensing by targeting hypoxia-inducible factors for ubiquitylation and proteasomal degradation. Early inactivation of VHL is commonly seen in clear-cell renal cell carcinoma (ccRCC), and insights gained from the functional analysis of pVHL have provided the foundation for the routine treatment of advanced-stage ccRCC with novel targeted therapies. However, recent sequencing studies have identified additional driver genes that are involved in the pathogenesis of ccRCC. As our understanding of the importance of VHL matures, it is timely to review progress from its initial description to current knowledge of VHL biology, as well as future prospects for novel medical treatments for VHL disease and ccRCC.

VHL, the story of a tumour suppressor gene

The epithelial to mesenchymal transition (EMT) is a biological process in which a non-motile epithelial cell changes to a mesenchymal phenotype with invasive capacities. This phenomenon has been well documented in multiple biological processes including embryogenesis, fibrosis, tumor progression and metastasis. The hallmark of EMT is the loss of epithelial surface markers, most notably E-cadherin, and the acquisition of mesenchymal markers including vimentin and N-cadherin. The downregulation of E-cadherin during EMT can be mediated by its transcriptional repression through the binding of EMT transcription factors (EMT-TFs) such as SNAIL, SLUG and TWIST to E-boxes present in the E-cadherin promoter. Additionally, EMT-TFs can also cooperate with several enzymes to repress the expression of E-cadherin and regulate EMT at the epigenetic and post- translational level. In this review, we will focus on epigenetic and post- translational modifications that are important in EMT. In addition, we will provide an overview of the various therapeutic approaches currently being investigated to undermine EMT and hence, the metastatic progression of cancer as well.

/pdf/regulation-of-epithelial-mesenchymal-transition-through-4qkeqr9q1p.pdf

Regulation of epithelial-mesenchymal transition through epigenetic and post-translational modifications.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/j.febslet.2012.02.037

Regulation of EMT by TGFβ in cancer.

Somatic cells can be reprogrammed into induced pluripotent stem cells biochemically through the expression of a few transcription factors. It is now shown that aligned microgrooves or nanofibres on cell-adhesive substrates can promote the reprogramming of somatic cells more efficiently through epigenetic regulation of genes related to pluripotency and the mesenchymal-to-epithelial transition. The findings suggest that the epigenetic state can be regulated by variations in cell morphology.

/pdf/biophysical-regulation-of-epigenetic-state-and-cell-1h2wdze3yp.pdf

鄧述諄(Shu-Chun Teng)

Papers

Interplay between HDAC3 and WDR5 Is Essential for Hypoxia-Induced Epithelial-Mesenchymal Transition

Interaction between HSP60 and beta-catenin promotes metastasis