(Boston)—PAX3 is a transcription factor (proteins involved in converting DNA into RNA) that drives melanoma progression by promoting cell growth, migration and survival, while inhibiting cellular terminal differentiation, which is the final stage where a cell becomes specialized and cell division ends. However, known PAX3 target genes are limited and cannot fully explain the wide impact of PAX3 function, suggesting that there are most likely many other genes that PAX3 controls that are undiscovered.
The PAX3 protein can regulate DNA through two separate binding domains, the paired domain (PD) and homeodomain (HD), which bind different DNA motifs , short recurring sequences within a DNA strand that regulate gene expression. It is not clear if these two domains bind and work together to regulate genes and if they promote all or only a subset of downstream cellular events.
A new study by researchers at Boston University Chobanian & Avedisian School of Medicine has discovered that PAX3 mainly uses the PD to bind to the DNA, and that it mostly turns on genes—many of which help cells grow and make other proteins – activities that support cancer growth.
"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," explains corresponding author Deborah Lang, PhD, associate professor of dermatology.
In an effort to see where PAX3 attaches to DNA in melanoma cells, the researchers created a computer program to predict how PAX3 touches the DNA – specifically, which part of the PAX3 protein is involved. They also checked whether the genes that PAX3 touched were turned on (active) or off (repressed).
The researchers believe that PAX3 could be a good target for treating melanoma, but currently, there are no drugs that block the function of this protein. "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," adds Lang.
These findings appear online in the journal Genes.
This research was funded by the Leo Foundation, LF-OC-21-00088; The American Cancer Society, DBG-23-1152683-01-RMC, TLC-24-1345883-01-TLC, and IRG-22-153-42-IRG-07; The National Institutes of Health/National Cancer Institute, 1R03CA288281-01A1, The National Institutes of Health/National Center for Advancing Translational Sciences and the Boston University Clinical and Translational Science Institute 1TL1TR001410 and 1UL1TR001430, and the Boston University Genome Science Institute (GSI) pilot project program.
