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.
Highlights
To date, melanoma is the most severe cutaneous cancer
Melanocyte differentiation and proliferation are dependent on mitogen-activated protein kinase (MAPK) signalling, which is tightly controlled by the binding of growth factors, such as stem cell factor (SCF), basic fibroblast growth factor and hepatocyte growth factor (HGF), to heterodimeric G
We describe the “phenotype-switching” model of melanoma cell plasticity and summarise the current data on the zinc-finger E-box-binding homeobox family of transcription factors (ZEBs) transcription factors in this melanoma progression model
Summary
Melanoma is the most severe cutaneous cancer. Its incidence rate is increasing and it has the highest mortality rate of all skin cancers [1]. Melanomas arise from melanocytes in which mutations typically target the proteins of the mitogen-activated protein kinase (MAPK) signalling pathway: BRAF (viral RAF murine sarcoma viral oncogene homolog B1) and NRAS (neuroblastoma RAS viral oncogene homolog). In melanoma cells harbouring BRAFV600E or NRASQ61K mutations, this signalling pathway is constitutively active, which results in uncontrolled cell growth [2]. It is becoming clear that a combination of (epi)genetic modifications, micro-environmental cues and reversible phenotypic changes within the melanoma cells are responsible for cellular plasticity. It appears that an intrinsic balance of the zinc-finger E-box-binding homeobox family of transcription factors (ZEBs) plays a central role in this melanoma cell plasticity. We describe the “phenotype-switching” model of melanoma cell plasticity and summarise the current data on the ZEB transcription factors in this melanoma progression model
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