BRD4 inhibitor suppresses melanoma metastasis via the SPINK6/EGFR-EphA2 pathway
Rui Hu, Yao Li, Ying Guo, Xin Li, Songtao Du, Mengting Liao, Huihui Hou, Hongyin Sun, Shuang Zhao, Juan Su, Xiang Chen, Mingzhu Yin
Abstract
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.