Melanoma is a serious form of skin cancer that begins in cells known as melanocytes. While it is less common than basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), melanoma is more dangerous because of its ability to spread to other organs more rapidly if it is not treated at an early stage. Researchers have known that the CRTC family of proteins (CRTC1, CRTC2, and CRTC3) is involved in pigmentation and melanoma, yet specific details of the proteins have been unknown. Now researchers at Salk Institute report new findings on the protein CRTC3, which can lead to new treatments for melanoma.

The researchers say they have uncovered a “genetic switch,” involving CRTC3, that seems to play a key role in the development of melanoma. Their findings are published in the journal Cell Reports in a paper titled, “Transcriptional co-activator regulates melanocyte differentiation and oncogenesis by integrating cAMP and MAPK/ERK pathways.”

“We’ve been able to correlate the activity of this genetic switch to melanin production and cancer,” explained corresponding study author Marc Montminy, MD, PhD, a professor in the Clayton Foundation Laboratories for Peptide Biology.

The researchers demonstrated that the deletion of the CRTC3 but not CRTC1 or CRTC2 genes affects pigmentation and melanocyte fitness.

“This is a really interesting situation where different behaviors of these proteins, or genetic switches, can actually give us specificity when we start thinking about therapies down the road,” said first author Jelena Ostojic, a former Salk staff scientist and now a principal scientist at DermTech.

The researchers also observed that when the protein was absent in melanoma cells, the cells migrated and invaded less. The team characterized, for the first time, the connection between two cellular communications (signaling) systems that converge on the CRTC3 protein in melanocytes.

These two systems tell the cell to either proliferate or make the pigment melanin.

“The fact that CRTC3 was an integration site for two signaling pathways—the relay race—was most surprising,” said Montminy. “CRTC3 makes a point of contact between them that increases specificity of the signal.”

Moving forward, the researchers would like to explore the mechanism of how CTRC3 impacts the balance of melanocyte differentiation to develop a better understanding of its role in cancer.

“Our results suggest that CRTC3 has a therapeutic benefit in the treatment of pigmentary disorders, cutaneous melanoma, and potentially other conditions characterized by dysregulated cAMP/MAPK crosstalk,” concluded the researchers.

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