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

doi:10.1016/j.phrs.2022.106609

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.

Authors

Rui Hu¹, Yao Li², Ying Guo³, Xin Li³, Songtao Du³, Mengting Liao⁴, Huihui Hou³, Hongyin Sun³, Shuang Zhao³, Juan Su³, Xiang Chen⁵, Mingzhu Yin⁶

Affiliations

¹ Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Department of Dermatology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China; National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Central South University, Changsha, Hunan 410008, China.
² Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA.
³ Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Central South University, Changsha, Hunan 410008, China.
⁴ Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Central South University, Changsha, Hunan 410008, China; Health Management of Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
⁵ Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Central South University, Changsha, Hunan 410008, China. Electronic address: [email protected].
⁶ Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Central South University, Changsha, Hunan 410008, China. Electronic address: [email protected].

PMID: 36516883
DOI: 10.1016/j.phrs.2022.106609

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