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

Pharmacol Res. 2023 Jan:187:106609. doi: 10.1016/j.phrs.2022.106609. Epub 2022 Dec 11.

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.

Keywords: BET inhibitor; BRD4; EGFR; EphA2; Melanoma; SPINK6.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents* / therapeutic use
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • ErbB Receptors
  • Humans
  • Melanoma* / metabolism
  • Nuclear Proteins / metabolism
  • Serine Peptidase Inhibitors, Kazal Type / therapeutic use
  • Transcription Factors / metabolism

Substances

  • Nuclear Proteins
  • Transcription Factors
  • Antineoplastic Agents
  • ErbB Receptors
  • BRD4 protein, human
  • Cell Cycle Proteins
  • EGFR protein, human
  • SPINK6 protein, human
  • Serine Peptidase Inhibitors, Kazal Type