Melanoma is the most aggressive and deadly form of skin cancer. Although early stage melanoma is curable by surgical removal, metastatic melanoma is notoriously difficult to treat. Understanding melanoma progression is therefore important. A recent theory proposes that melanoma cells undergo a reversible switch from proliferative to invasive phenotypes, and that this phenotype switch is responsible for driving the tumorigenic (proliferative) and disseminating (invasive) phases of disease progression. Microphthalmia-associated Transcription Factor (MITF), a master regulator of gene expression in melanocytic cells, is known to be responsible for the phenotype switch. However, the downstream MITF target genes directly responsible for mediating changes in melanoma cell behaviour are less well known. In a previous study Rab27a (an MITF target gene) was identified as a tumour “driver” gene. Rab GTPases are a family of proteins that regulate vesicular transport. Altered expression of Rabs and aberrant protein trafficking has been associated with several types of cancer.
Our data revealed increased expression of Rab27a in melanoma cells with a proliferative phenotype. We show that shRNA knockdown of Rab27a inhibits growth and increases cell death, consistent with a role for Rab27a in melanoma cell proliferation and perhaps also programmed cell death. Rab27a knockdown altered cell morphology – suggesting a potential role in cell movement, however 2D migration was unaffected. Notably, Rab27a knockdown decreased invasion in our 3D melanoma spheroid model. In contrast, MITF knockdown resulted in increased invasion, while also decreasing proliferation, consistent with its role in phenotype switching. This suggests that while Rab27a may be involved in MITF-mediated proliferation, other MITF target genes mask the effect of Rab27a loss on invasion in MITF-depleted cells. Given that loss of Rab27a decreased both melanoma growth and invasion, this protein would be an attractive target for melanoma therapies.