BRAFi induced demethylation of miR-152-5p regulates phenotype switching by targeting TXNIP in cutaneous melanoma

• DOI: 10.1007/s10495-019-01586-0
• Publication Date: 2020-02-13T13:03:01Z
• Authors: Kezhu Li; Mingrui Tang; Shuang Tong; Chenchao Wang; Qiang Sun; Mengzhu Lv; Xu Sun; Ting Wang; Shifeng Jin
• Keywords: Male; Proto-Oncogene Proteins B-raf; 0303 health sciences; Skin Neoplasms; Cell Cycle; Middle Aged; Demethylation; 3. Good health; Gene Expression Regulation, Neoplastic; MicroRNAs; 03 medical and health sciences; Vemurafenib; Cell Movement; Drug Resistance, Neoplasm; Cell Line, Tumor; Mutation; Humans; Female; Neoplasm Metastasis; Carrier Proteins; Promoter Regions, Genetic; Melanoma; Protein Kinase Inhibitors

Treatment of advanced BRAFV600-mutant melanoma using BRAF inhibitors (BRAFi) eventually leads to drug resistance and selects for highly metastatic tumor cells. We compared the most differentially dysregulated miRNA expression profiles of vemurafenib-resistant and highly-metastatic melanoma cell lines obtained from GEO DataSets. We discovered miR-152-5p was a potential regulator mediating melanoma drug resistance and metastasis. Functionally, knockdown of miR-152-5p significantly compromised the metastatic ability of BRAFi-resistant melanoma cells and overexpression of miR-152-5p promoted the formation of slow-cycling phenotype. Furthermore, we explored the cause of how and why miR-152-5p affected metastasis in depth. Mechanistically, miR-152-5p targeted TXNIP which affected metastasis and BRAFi altered the methylation status of MIR152 promoter. Our study highlights the crucial role of miR-152-5p on melanoma metastasis after BRAFi treatment and holds significant implying that discontinuous dosing strategy may improve the benefit of advanced BRAFV600-mutant melanoma patients.