Emerging Transcriptional Mechanisms in the Regulation of Epithelial to Mesenchymal Transition and Cellular Plasticity in the Kidney

Abstract Cellular plasticity and transitional phenotypes add to complexities of cancer metastasis that can be initiated by single cell epithelial to mesenchymal transition (EMT) or cooperative cell migration (CCM). Our study identifies novel regulatory cross-talks between Tcf21 and Slug in mediating phenotypic and migration plasticity in high-grade serous ovarian adenocarcinoma (HGSC). Differential expression and subcellular localization associate Tcf21, Slug with epithelial, mesenchymal phenotypes, respectively; however, gene manipulation approaches identify their association with additional intermediate phenotypic states, implying the existence of a multistep epithelial-mesenchymal transition program. Live imaging further associated distinct migratory modalities with the Tcf21/Slug status of cell systems and discerned proliferative/passive CCM, active CCM and EMT modes of migration. Tcf21–Slug balance identified across a phenotypic spectrum in HGSC cell lines, associated with microenvironment-induced transitions and the emergence of an epithelial phenotype following drug exposure. Phenotypic transitions and associated functionalities following drug exposure were affirmed to ensue from occupancy of Slug promoter E-box sequences by Tcf21. Our study effectively provides a framework for understanding the relevance of ovarian cancer plasticity as a function of two transcription factors.

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Functional Balance between TCF21-Slug defines phenotypic plasticity and sub-classes in high-grade serous ovarian cancer

10.1101/307934 ◽

2018 ◽

Cited By ~ 4

Author(s):

Sagar S Varankar ◽

Swapnil C Kamble ◽

Avinash M Mali ◽

Madhuri M More ◽

Ancy Abraham ◽

...

Keyword(s):

Cancer Metastasis ◽

Epithelial To Mesenchymal Transition ◽

High Grade ◽

Cellular Plasticity ◽

Ovarian Adenocarcinoma ◽

Mesenchymal Transition ◽

Functional Balance ◽

And Migration ◽

Sheet Migration

AbstractCellular plasticity and transitional phenotypes add to complexities of cancer metastasis initiated by single cell epithelial to mesenchymal transition or cooperative cell migration (CCM). We identified novel regulatory cross-talks between Tcf21 and Slug in mediating phenotypic and migration plasticity in high-grade serous ovarian adenocarcinoma. Live imaging discerned CCM as being achieved either through rapid cell proliferation or sheet migration. Transitional states were enriched over the rigid epithelial or mesenchymal phenotypes under conditions of environmental stresses. The Tcf21-Slug interplay identified in HGSC tumors through effective stratification of subtypes also contributed to class-switching in response to disease progression or therapy. Our study effectively provides a framework for understanding the relevance of cellular plasticity in situ as a function of two transcription factors.

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Intrinsic Balance between ZEB Family Members Is Important for Melanocyte Homeostasis and Melanoma Progression

Cancers ◽

10.3390/cancers12082248 ◽

2020 ◽

Vol 12 (8) ◽

pp. 2248 ◽

Cited By ~ 1

Author(s):

Kenneth Bruneel ◽

Jeroen Verstappe ◽

Niels Vandamme ◽

Geert Berx

Keyword(s):

Transcription Factors ◽

Epithelial To Mesenchymal Transition ◽

Therapy Resistance ◽

Resistant Cell ◽

Cellular Plasticity ◽

Mesenchymal Transition ◽

Cell State ◽

Promising Therapeutic Target ◽

Main Driver ◽

Mitf Expression

It has become clear that cellular plasticity is a main driver of cancer therapy resistance. Consequently, there is a need to mechanistically identify the factors driving this process. The transcription factors of the zinc-finger E-box-binding homeobox family, consisting of ZEB1 and ZEB2, are notorious for their roles in epithelial-to-mesenchymal transition (EMT). However, in melanoma, an intrinsic balance between ZEB1 and ZEB2 seems to determine the cellular state by modulating the expression of the master regulator of melanocyte homeostasis, microphthalmia-associated transcription factor (MITF). ZEB2 drives MITF expression and is associated with a differentiated/proliferative melanoma cell state. On the other hand, ZEB1 is correlated with low MITF expression and a more invasive, stem cell-like and therapy-resistant cell state. This intrinsic balance between ZEB1 and ZEB2 could prove to be a promising therapeutic target for melanoma patients. In this review, we will summarise what is known on the functional mechanisms of these transcription factors. Moreover, we will look specifically at their roles during melanocyte-lineage development and homeostasis. Finally, we will overview the current literature on ZEB1 and ZEB2 in the melanoma context and link this to the ‘phenotype-switching’ model of melanoma cellular plasticity.

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Epithelial-to-Mesenchymal Transition: Epigenetic Reprogramming Driving Cellular Plasticity

Trends in Genetics ◽

10.1016/j.tig.2017.08.004 ◽

2017 ◽

Vol 33 (12) ◽

pp. 943-959 ◽

Cited By ~ 88

Author(s):

Nicolas Skrypek ◽

Steven Goossens ◽

Eva De Smedt ◽

Niels Vandamme ◽

Geert Berx

Keyword(s):

Epithelial To Mesenchymal Transition ◽

Epigenetic Reprogramming ◽

Cellular Plasticity ◽

Mesenchymal Transition

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The role of DUBs in the post-translational control of cell migration

Essays in Biochemistry ◽

10.1042/ebc20190022 ◽

2019 ◽

Vol 63 (5) ◽

pp. 579-594 ◽

Cited By ~ 2

Author(s):

Guillem Lambies ◽

Antonio García de Herreros ◽

Víctor M. Díaz

Keyword(s):

Cell Migration ◽

Translational Control ◽

Epithelial To Mesenchymal Transition ◽

Extracellular Matrix Remodeling ◽

Matrix Remodeling ◽

Mesenchymal Transition ◽

Tgfβ Receptors ◽

Fundamental Process ◽

Multistep Process

Abstract Cell migration is a multifactorial/multistep process that requires the concerted action of growth and transcriptional factors, motor proteins, extracellular matrix remodeling and proteases. In this review, we focus on the role of transcription factors modulating Epithelial-to-Mesenchymal Transition (EMT-TFs), a fundamental process supporting both physiological and pathological cell migration. These EMT-TFs (Snail1/2, Twist1/2 and Zeb1/2) are labile proteins which should be stabilized to initiate EMT and provide full migratory and invasive properties. We present here a family of enzymes, the deubiquitinases (DUBs) which have a crucial role in counteracting polyubiquitination and proteasomal degradation of EMT-TFs after their induction by TGFβ, inflammatory cytokines and hypoxia. We also describe the DUBs promoting the stabilization of Smads, TGFβ receptors and other key proteins involved in transduction pathways controlling EMT.

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