When cancer cells colonize vital organs, they enter hostile territory, making it difficult to metastasize. Melanoma cells, for instance, experience high levels of oxidative stress in the bloodstream and at distant sites that kill most metastasizing cells before they can form new tumors. But what enables cancer cells to escape the effects of oxidative stress and spread? A study now published in Nature Cancer, details a mechanism that allows metastasizing melanoma cells to withstand this stress. While the proteins in the body are usually constructed from 20 common amino acids, the researchers identified an enzyme called FTSJ1, that chemically tags the tRNA molecule carrying the special amino acid selenocysteine. This modification called methlyation prompts the cancer cells to produce selenocysteine-containing proteins to cope with oxidative stress.
This new study builds on Dr. Piskounova’s previous research which demonstrated oxidative stress suppresses metastasis in melanoma. However, the current paper showed that some metastatic cells have increased levels of FTSJ1, which in turn increases the production of selenoproteins and the potential for these cells to metastasize. Selenocysteine-containing proteins play a central role in redox homeostasis. Their translation is a highly regulated process and is dependent on two tRNA-selenocysteine isodecoders differing by a single 2′-O-ribose methylation called Um34. FTSJ1 has now been identified as the Um34 methyltransferase required for efficient selenocysteine insertion at the UGA stop codon during translation. Moreover, FTSJ1 mediates efficient translation of selenoproteins essential for the cellular antioxidant response.
Working with laboratory grown melanoma cells and animal models, the researchers found that knocking out FTSJ1 turned off the defense mechanism, making melanoma cells vulnerable to oxidative stress. Indeed, FTSJ1 is necessary for promoting metastasis in animal models of melanoma. The results suggest that therapies targeting FTSJ1 may prevent or treat metastasis with few side effects to normal tissues since FTSJ1 is only needed during early brain development. Blocking metastasis is critical since the five-year survival rate for people whose melanoma is detected and treated before it spreads is greater than 99% but drops to 35%, once the cancer has spread to other organs, according to the American Cancer Society. Therefore, FTSJ1 could become a potential therapeutic target specific for metastatic disease.
Currently, Dr. Piskouvnova and her colleagues are working on developing small molecules that inhibit FTSJ1. They also want to repeat their studies in pancreatic cancer cells to determine if similar mechanisms control metastasis in other types of cancer.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
Nease LA et al. Nature Cancer 2024 Oct 22; in press.
Suzuki T. Nat Rev Mol Cell Biol. 2021; 22:375–392.
Hatfield DL et al. Trends Biochem Sci. 2014; 39:112.