New research published by researchers from Boston University explores the role of PAX3, a protein involved in gene regulation, in controlling skin melanoma genes. The study, published in the Open Access journal Genes, identifies key novel PAX3 regulatory regions and binding sites in the genes of melanoma cell lines.

PAX3 is normally important for the development and growth of pigment cells called melanocytes, but in melanoma it is too active and helps cancer grow. What’s new about our study is that we used a broad and detailed approach to see exactly where PAX3 sits on the DNA in melanoma cells – something that hasn’t been done before in this way – corresponding author Deborah Lang, PhD, associate professor of dermatology.

Development of melanoma

Melanoma is an aggressive type of skin cancer that can spread to other organs and parts of the body if left untreated. It is one of the most invasive types of cancers and has the highest risk of death; however can be cured if caught and treated early.

A UK study found that around 86% of melanoma cases were caused by the sun. The risk of developing melanoma or non-melanoma skin cancer (a more common and less aggressive form of skin cancer) can be significantly reduced by being safe in the sun. This means applying sunscreen and avoiding the sun’s UV rays, which are the strongest at the peak hours of midday to early afternoon.

According to the Skin Cancer Foundation, the number of melanoma diagnoses is expected to increase by 5.9% in 2025 alone. Understanding the mechanisms behind the development and progression of melanoma is critical to saving lives from one of the most fatal cancer types. In this study, we learn how researchers identified the significant role of PAX3 in regulating melanoma genes.

PAX3 in development

PAX3 is a type of transcription factor. This means that it’s involved in regulating gene expression, i.e., it helps to increase or decrease the expression of a particular gene. According to the existing literature, PAX3 is present in the developing nervous system of embryos – this is called the neural crest. Here, PAX3 is critical for cell differentiation & maturation – these are processes by which cells divide and change to turn into more specific cells to carry out their specified functions.

For example, neural crest cells differentiate into melanocyte stem cells, which in turn differentiate into functional melanocytes (melanin producing cells primarily in the skin). Normal PAX3 activity is vital for the normal differentiation, growth and maintenance of melanocytes. However, previous experiments have shown that overactivation of PAX3 activity induces overgrowth and uncontrolled division of melanocytes, inducing melanoma development.

Learning how PAX3 interacts with melanoma genes

In the mentioned study, researchers looked at the specific DNA binding sites of the PAX3 protein associated with melanoma growth and survival. The researchers used the human melanoma cell line SK-MEL-5 and identified known PAX3 target genes, such as MITF.

As part of the study, they created an in-house script to determine which region of the PAX3 protein binds to specific DNA sequences. The study confirmed that PAX3 also interacted with other gene regulatory elements, co-factor,associated with cell growth, function and signalling, inducing cell activation and division. Altogether, the study revealed a distinctive PAX3 regulatory gene signature in melanoma cells, which could be essential in both future diagnostics and therapeutics.

Targeting PAX3 binding sites

Since PAX3 overactivation is associated with the development of melanoma, it would therefore make an ideal drug target. However, there are currently no drugs targeting PAX3 specifically.

Since we found that PAX3 works mostly through its paired domain, designing drugs that block this part of the protein could be an effective way to treat melanoma. – Deborah Lang.

The study, therefore, highlights specific regions in which PAX3 interacts with the DNA of melanoma, providing a foundation for the development of effective therapeutics.

Access the journal Genes for more research like this, or see the full MDPI journal list