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Researchers have found a new role for the SHARPIN protein. In addition to being one of three proteins in the linear ubiquitin chain assembly complex (LUBAC), regulating NFκB and other inflammatory molecules, SHARPIN modulates PRMT5, an epigenetic master switch that controls several proteins linked to melanoma.
SHARPIN, is best known for its role in LUBAC, which plays a direct role in inflammatory signaling. However, SHARPIN has a second life, regulating PRMT5, which methylates individual genes and the histones that package DNA, controlling a wide range of gene expression. PRMT5 has been linked to prostate, breast, lung and other cancers.
Using human melanoma cell lines, the researchers found that SHARPIN (but not fellow LUBAC proteins HOIP and HOIL-1L) increases PRMT5 activity, which boosts transcription factors SOX10, PAX3 and MITF, all of which contribute to melanoma growth. The researchers believe SHARPIN fine-tunes PRMT5, affecting how the enzyme methylates certain proteins, but not histones.
SHARPIN serves as a navigator, showing PRMT5 where to go and thus which proteins to methylate.
SHARPIN becomes important in tumors that have lost proteins CDKN2A and MTAP, which are co-deleted in around 15 percent of all cancers. When MTAP is deleted, PRMT5 activity is reduced. However, in those cases SHARPIN acts as a counterbalance, boosting PRMT5. Epidemiological data show that patients whose tumors lack MTAP, and have elevated levels of SHARPIN, have poorer prognosis.
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