Researchers have identified a protein called CPEB4 that seems to be crucial in establishing melanoma’s intrinsic signature and in driving the development of these aggressive tumors.
The study, “Lineage-specific roles of the cytoplasmic polyadenylation factor CPEB4 in the regulation of melanoma drivers,” published in Nature Communications, suggests that CPEB4 may be a promising therapeutic target for melanoma patients.
“In previous studies, we have demonstrated that melanomas are very different from other types of tumors in that they activate mechanisms of self-degradation (autophagy), or control the internalization and secretion of molecules, for example,” Marisol Soengas, senior author of the paper and an expert in the field of melanoma identity, said in a press release.
However, understanding which mechanisms drive the particular aggressive behavior of melanomas has been hindered by the high mutation rate found in these tumors. Now, the researchers have found that CPEB4 plays a critical role in establishing melanoma’s characteristic behavior.
The CPEB family of proteins is known to regulate gene expression by participating in the process of mRNA stabilization in the nucleus. Consistently, these proteins are associated with a multitude of cellular processes, including cell proliferation, differentiation, polarity, and motility.
The expression of CPEBs in cancer is highly variable, with pro- and anti-tumorigenic roles reported depending on the system, most likely because these proteins can both stabilize and destabilize mRNA molecules. CPEB4 caught the attention of researchers because of its overexpression in gliomas and pancreatic cancers, which are also aggressive cancers.
After performing computer and histological analysis, the researchers found that CPEB4 was increased early in melanoma progression, suggesting that this protein could be involved in cell proliferation.
Their results then revealed that melanoma is dependent on CPEB4 in a manner not shared by other tumors. In melanoma, CPEB4 was found to control lineage-specificity through two distinct mechanisms: activation of genes that are unique to this tumor type and distinct regulation of factors that are also common to other cancers.
Indeed, CPEB4 was able to modulate the expression of MITF and RAB27A, which are both essential drivers of this tumor type, and to enrich the expression of key tumor-promoting signaling pathways.
This data provides new insight on the mechanisms underlying melanoma progression, suggesting that CPEB4 is a main driver of the melanoma-specific signature, and that CPEB4-controlled pathways could represent a melanoma vulnerability that could be exploited therapeutically.