Melanoma plasticity is controlled by a TRIM28-JUNB mediated switch

The introduction of immune checkpoint blockade has revolutionized the treatment of metastatic melanoma1. However, 40-60% of patients with metastatic melanoma do not respond to immune checkpoint blockade, and a significant fraction of patients acquire resistance to treatment2,3. This resilience and aggressiveness of melanoma tumors is partly due to their ability to switch between invasive and proliferative states4,5. The transition between phenotypic states indicates that phenotype switching occurs through reversible epigenetic mechanisms rather than by acquisition of mutations6,7. Identifying the epigenetic mechanisms that underlie phenotype switching of melanoma cells could potentially lead to new therapeutic strategies. Here we report that the bromodomain protein TRIM28 (KAP1/TIF1{beta}) regulates a JUNB dependent phenotypic switch in melanoma cells. Knockdown of TRIM28 in melanoma cells reduced the expression of pro-invasive YAP1 signature genes, and led to reduced invasiveness and lung colonization. In contrast, TRIM28 knockdown increased the expression of KRAS signature genes and promoted tumor growth. TRIM28 interacted with the transcriptional elongation factors CDK9 and HEXIM1, and negatively regulated the transcriptional elongation of JUNB by RNA polymerase II. Rescue experiments demonstrated that the effects of TRIM28 knockdown were directly mediated by JUNB. Mechanistically, JUNB played a pivotal role in phenotype switching by inhibiting the invasiveness of melanoma cells and increasing the growth of melanoma tumors. Our results contribute to the understanding of melanoma plasticity, and suggest that cancer drugs inhibiting the transcriptional elongation of RNA polymerase II should be carefully evaluated in melanoma to exclude the risk for increased metastasis.