biostudies-literatureUnknown13Wu HZBRAF inhibitors are commonly used in targeted therapies for melanoma patients harboring BRAF^V600E mutant. Despite the benefit of vemurafenib therapy, acquired resistance during or after treatment remains a major obstacle in BRAF^V600E mutant melanoma. Here we found that RSK2 is overexpressed in melanoma cells and the high expression of RSK2 indicates poor overall survival (OS) in melanoma patients. Overexpression of RSK2 leads to vemurafenib resistance, and the deletion of RSK2 inhibits cell proliferation and sensitizes melanoma cells to vemurafenib. Mechanistically, RSK2 enhances the phosphorylation of FOXO1 by interacting with FOXO1 and promoting its subsequent degradation, leading to upregulation of cyclin D1 in melanoma cells. These results not only reveal the presence of a RSK2-FOXO1-cyclin D1 signaling pathway in melanoma, but also provide a potential therapeutic strategy to enhance the efficacy of vemurafenib against cancer.Frontiers in pharmacology950571https://www.ebi.ac.uk/biostudies/studies/S-EPMC9541206biostudies-literatureRSK2 promotes melanoma cell proliferation and vemurafenib resistance <i>via</i> upregulating cyclin D1.PMC9541206Sun XYLi ZJiang SLWu HZLi YZShi XMCheng YLi LYfalseRSK2 promotes melanoma cell proliferation and vemurafenib resistance <i>via</i> upregulating cyclin D1.BRAF inhibitors are commonly used in targeted therapies for melanoma patients harboring BRAF^V600E mutant. Despite the benefit of vemurafenib therapy, acquired resistance during or after treatment remains a major obstacle in BRAF^V600E mutant melanoma. Here we found that RSK2 is overexpressed in melanoma cells and the high expression of RSK2 indicates poor overall survival (OS) in melanoma patients. Overexpression of RSK2 leads to vemurafenib resistance, and the deletion of RSK2 inhibits cell proliferation and sensitizes melanoma cells to vemurafenib. Mechanistically, RSK2 enhances the phosphorylation of FOXO1 by interacting with FOXO1 and promoting its subsequent degradation, leading to upregulation of cyclin D1 in melanoma cells. These results not only reveal the presence of a RSK2-FOXO1-cyclin D1 signaling pathway in melanoma, but also provide a potential therapeutic strategy to enhance the efficacy of vemurafenib against cancer.2022-01-01T00:00:00Z20222025-04-22T21:52:17.341Z2025-02-19T01:27:42.794ZS-EPMC95412063621084310.3389/fphar.2022.950571