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

Abstract

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.

The Post-Translational Regulation of Epithelial–Mesenchymal Transition-Inducing Transcription Factors in Cancer Metastasis

“…Nucleosome remodeling and deacetylation (NuRD) complexes contains HDAC1/2 and chromodomain helicase DNA-binding proteins [ 185 ]. The NuRD complex binds to both ZEB1 and ZEB2 [ 186 ]. This complex binds to the NuRD-interacting motif that is close to the N-terminal of ZEB2 [ 186 ].…”

“…The NuRD complex binds to both ZEB1 and ZEB2 [ 186 ]. This complex binds to the NuRD-interacting motif that is close to the N-terminal of ZEB2 [ 186 ]. The domains of ZEB1 that interact with the NuRD complex are not known [ 187 ].…”

The genetic and epigenetic basis of distinct melanoma types

“…Multiple extracellular factors have been identified that induce the phenotypic switch toward an invasive phenotype, including hypoxia, low nutrient (low glucose and amino acid limitation), and inflammatory signaling, including TGFβ and tumor necrosis factor α (TNFα), etc., in addition to cell intrinsic factors (e.g. oncogenic drivers) 13,84 . Also, it is becoming evident that epigenetic modifications to suppress the expression of MITF and its targets and therapeutic interventions (i.e.…”

Lineage Plasticity in Cancer: The Tale of a Skin-walker

“…Another important family of transcription factors, the zinc-finger E-box-binding homeobox family of transcription factors (ZEBs) ZEB1 and ZEB2 are known for their ability to induce EMT-driven cellular plasticity in carcinoma progression [163,164]. However, in melanoma, ZEB1 and ZEB2 function antagonistically and play a central role in "phenotype switching" by modulating the expression of microphthalmia-associated transcription factor (MITF), a master regulator of melanocyte homeostasis and differentiation.…”

“…However, in melanoma, ZEB1 and ZEB2 function antagonistically and play a central role in "phenotype switching" by modulating the expression of microphthalmia-associated transcription factor (MITF), a master regulator of melanocyte homeostasis and differentiation. Increased ZEB2 expression drives the expression of MITF leading to a differentiated and proliferative cell state whereas increased ZEB1 expression lowers MITF and leads to a stem-like and invasive cell state [163,[165][166][167].…”