The CoREST Repressor Complex Mediates Phenotype Switching and Therapy Resistance in Melanoma
The CoREST Repressor Complex Mediates Phenotype Switching and Therapy Resistance in Melanoma
Abstract Virtually all patients with BRAF-mutant melanoma develop resistance to MAPK inhibitors largely through non-mutational events1,2. Although the epigenetic landscape has been shown to be altered in therapy-resistant melanomas and other cancers3,4, a specific targetable epigenetic mechanism regulating treatment resistance has not been validated to date. Here we evaluate the CoREST repressor complex and the novel inhibitor, corin5, within the context of melanoma phenotype plasticity and therapeutic resistance in order to define epigenetic mechanisms underlying these processes. We find that CoREST is a critical mediator of the major distinct melanoma phenotypes and that corin treatment of melanoma cells leads to phenotype reprogramming. We further demonstrate that treatment of BRAF inhibitor (BRAFi)-resistant melanomas with corin leads to resensitization of tumor cells to BRAFi. Among the transcriptional targets of CoREST in melanoma are the dual-specificity phosphatases (DUSPs). DUSP1 is shown to be consistently downregulated in BRAFi-resistant melanomas which can be reversed by corin treatment, thereby leading to downstream inhibition of p38 MAPK activity and resensitization of resistant cells to targeted BRAFi therapies. These findings identify the CoREST repressor complex as a central mediator of melanoma phenotype plasticity and resistance to targeted therapy and suggest that CoREST inhibitors may prove beneficial to patients with BRAF-mutant melanomas who have acquired BRAFi-resistance.
Hanly Ailish、Kuang Kevin、Collard Marianne、Cole Matthew、Agus Filisia、Labadorf Adam、Cole Philip A、Alani Rhoda M.、Wu Muzhou、Gibson Frederick、Xiao Amy、Kalin Jay、Nocco Sarah
Department of Dermatology, Boston University School of MedicineDepartment of Dermatology, Boston University School of MedicineDepartment of Dermatology, Boston University School of MedicineDepartment of Dermatology, Boston University School of MedicineBioinformatics Program, Boston University||Department of Neurology, Boston University School of MedicineBioinformatics Program, Boston University||Department of Neurology, Boston University School of MedicineDivision of Genetics, Departments of Medicine and Biological Chemistry and Molecular Pharmacology, Harvard Medical School and Brigham and Women?ˉs HospitalDepartment of Dermatology, Boston University School of MedicineDepartment of Dermatology, Boston University School of MedicineDepartment of Dermatology, Boston University School of MedicineDepartment of Dermatology, Boston University School of MedicineDivision of Genetics, Departments of Medicine and Biological Chemistry and Molecular Pharmacology, Harvard Medical School and Brigham and Women?ˉs HospitalDepartment of Dermatology, Boston University School of Medicine
肿瘤学基础医学分子生物学
Hanly Ailish,Kuang Kevin,Collard Marianne,Cole Matthew,Agus Filisia,Labadorf Adam,Cole Philip A,Alani Rhoda M.,Wu Muzhou,Gibson Frederick,Xiao Amy,Kalin Jay,Nocco Sarah.The CoREST Repressor Complex Mediates Phenotype Switching and Therapy Resistance in Melanoma[EB/OL].(2025-03-28)[2025-06-17].https://www.biorxiv.org/content/10.1101/2020.09.30.320580.点此复制
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