BRD4 inhibitor suppresses melanoma metastasis via the SPINK6/EGFR-EphA2 pathway.

BET inhibition or BRD4 depletion is a promising and attractive therapy for metastatic melanoma; however, the mechanism is still unclear. Here, we indicated that BET inhibition suppressed melanoma metastasis both in vitro and in vivo and identified a new mechanism by which BET inhibitors suppress melanoma metastasis by blocking the direct interaction of BRD4 and the SPINK6 enhancer. Moreover, we demonstrated that SPINK6 activated the EGFR/EphA2 complex in melanoma and the downstream ERK1/2 and AKT pathways. Thus, these results identified the SPINK6/EGFR-EphA2 axis as a new oncogenic pathway in melanoma metastasis and support the further development of BRD4 inhibitors for the treatment of metastatic melanoma in the clinic.