Melanocytes, Melanoma and MITF

Susana Fares Mazloum

We have several transcription factors that play important roles when it comes to the development, specification, control and differentiation of different cell types in our body. One of these is microphthalmia-associated transcription factor (MITF), which plays a key role in melanocyte development and differentiation. In this article, I will discuss the basic biological features and the role of MITF within melanocytes (skin cells) and melanoma (aggressive skin cancer).

History

paula hertwig
Geneticist Paula Hertwig. Image source: WIKIPEDIA

In 1942, geneticist Paula Hertwig observed that the offspring of an X-Ray irradiated mouse had microphthalmia (abnormally small eyes) and abnormal pigmentation on their bodies. She called the mutant locus ‘mi’, which is currently known as MITF. With time, additional characteristics of this mutant locus were also observed, such as hearing loss caused by the lack of melanocytes in the cochlea (inner ear) and mutations in mast cells and osteoclasts (cells that break down bone tissue).

In 1993, using transgenic insertional mutagenesis (creation of mutations of DNA by the addition of one or more base pairs), scientists were able to identify the ‘MITF gene’ as the gene responsible for all the ‘mi’ phenotypes and molecular studies revealed that MITF functioned as a DNA-binding transcription factor capable of recognizing and regulating a sequence element that was essential for expression of the pigmentation gene. One year later, the mutations related to MITF were finally identified and described.

Another thing research has shown is that MITF has many isoforms. There are 9 isoforms; they all differ in exon 1 and are identical from exons 2 to 9. The MITF that discussed in this article is MTF-M which is melanocyte specific, meaning that it is exclusively expressed in melanocytes and melanoma cells.

 

isoforms
MITF isoforms. Credit: Akinori Kawakami & David E Fisher

 

What exactly do we know about MITF, nowadays?

We know that:

▪MITF is a class E basic-loop-helix-leucine-zipper protein.

▪MITF is encoded by the MITF gene, which in turn, is located in the short arm of chromosome 3 in position 13.

gene
MITF gene location. Credit: NIH.

▪The function of MITF is to target genes that are responsible for differentiation, homeostasis maintenance, cell cycle and anti-apoptotic (cell survival) activities within melanocytes.

▪Mutations or over-expression of MITF can lead to serious health concerns such as Waardenburg syndrome, which is characterized by varying degrees of deafness and pigmentation abnormalities of the eye, hair and skin. It may also lead to an oncogenic event that can be seen in familial or sporadic melanoma.

Melanocytes, Melanoma and MITF

melanoma
Melanoma. Credit: News Medical

As research has proven, melanoma cells are derived from melanocytes and all the pro-survival mechanisms provided by MITF that counteract damage-causing factors already available in melanocytes are further extended in melanoma cells. In other words, melanoma cells take advantage of all the abilities of MITF within melanocytes and use them for their own benefit and survival. Thus, the factor ends up acting like a lineage survival and lineage addiction oncogene. Although MITF seems to play an important role in melanoma, the case percentage of MITF melanoma is estimated to be only 20% and mostly appears as amplifications (over-expression).

Moreover, the process that leads to MITF transcription is the same in both melanocytes and melanoma cells. First, there are signaling pathways that activate MITF transcription. After being transcribed, MITF initiates gene targeting according to the signals received, leading to post-translational modifications that will result in the expression of a required activity such as inhibition or progression of the cell cycle. Genes targeted by MITF in melanocytes and melanoma are the same; the difference lies within the level and frequency of the gene expression.

Curiosity

One curious thing research has shown is that humans suffer from both high and low MITF melanoma. MITF-low tumors tend to be more aggressive and invasive whereas MITF-high tumors tend to be more proliferative and thereby less invasive. Thus, MITF can be expressed in different levels in the same tumor. This might be an explanation on why some tumors are treatment resistant. However, more research on the subject is needed as scientists still cannot explain why MITF-low melanoma is more aggressive.

Now, an important question: Can we target MITF to treat melanoma?

There has been extensive research on this subject. The results so far are:

▪HDAC (a group of enzymes) inhibitors were seen to repress MITF-M transcription

▪Inhibition of MITF deubiquitination promotes MITF degradation

▪Nelfinavir, a human immunodeficiency virus drug, repressed MITF transcription

In conclusion, advances in our understanding of the biological functions of the MITF transcription factor have revealed fundamental insights into basic biology of pigmentation, melanocyte development, and melanoma.

Edited by: Mehek Dedhia and Shreya Singireddy