Transcriptional regulation by AP-2α during melanoma metastasis

Melanoma patients have generally favorable clinical outcomes prior to progressing to metastatic disease. However, metastatic melanoma is a very aggressive cancer that is exceedingly difficult to treat. Therefore, studying the biological mechanisms causing a melanoma to become metastatic are likely to provide significant benefits to patients. In this manuscript, we describe experiments we performed that led us to conclude a transcription factor known as AP-2α drives melanoma cells to metastasize. Transcription factors are proteins that control expression of a substantial number of genes, so targeting them directly with drugs raises the likelihood of unforeseen outcomes in patients. Therefore, we turned our attention to determining which specific genes AP-2α controls to drive melanoma metastasis.

We determined AP-2α facilitates metastasis by driving high expression of genes within the E2F pathways, including the oncogene EZH2. Mechanistically, the resulting high expression of EZH2 drives a melanoma to become metastatic. Interestingly, there is a drug (tazemetostat) that inhibits EZH2 and was recently FDA-approved for the treatment of other metastatic cancers that are likewise difficult to treat, comparable to melanoma. Encouragingly, we used this inhibitor to treat melanoma cells and it substantially reduced cellular behaviors that represent metastatic capability. Further promising, we treated mice that have melanoma with this drug and it substantially reduced metastatic ability of their tumors. Tazemetostat is a highly specific inhibitor of EZH2, and we show EZH2 is very highly expressed in melanomas but not healthy tissue, it is likely this inhibitor will have profound effects on the tumor while having limited side effects on healthy tissues.