BRD4 inhibitor suppresses melanoma metastasis via the SPINK6/EGFR-EphA2 pathway. (January 2023)

• Record Type: Journal Article
• Authors: Hu, Rui; Li, Yao; Guo, Ying; Li, Xin; Du, Songtao; Liao, Mengting; Hou, Huihui; Sun, Hongyin; Zhao, Shuang; Su, Juan; Chen, Xiang; Yin, Mingzhu
• Is Part Of: Pharmacological research. Volume 187(2023)
• Publication Date: 2023-01
• Subjects: Melanoma -- BET inhibitor -- BRD4 -- SPINK6 -- EphA2 -- EGFR; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2022.106609
• Languages: English
• ISSNs: 1043-6618

Abstract

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. Graphical Abstract: ga1 Highlights: BET inhibitors suppress melanoma metastasis by regulating SPINK6. BRD4 mediates SPINK6 expression by directly binding to its enhancer region. SPINK6 activated ERK/AKT signaling via EGFR and EphA2 in melanoma.