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

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Abstract

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.

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Authors and Affiliations

  1. Department of Plastic Surgery, the First Affiliated Hospital of China Medical University, No.155, Nan**g North Street, Shenyang City, 110001, Liaoning, China

    Kezhu Li, Mingrui Tang, Shuang Tong, Chenchao Wang, Qiang Sun, Mengzhu Lv, Xu Sun, Ting Wang & Shifeng **

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  1. Kezhu Li
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  2. Mingrui Tang
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  3. Shuang Tong
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  4. Chenchao Wang
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  6. Mengzhu Lv
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  7. Xu Sun
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  8. Ting Wang
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  9. Shifeng **
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KL and SJ conceived and designed the experiments; KL, MT, ST, CW and QS performed the experiments; KL, ML, XS and TW analyzed the data; KL and SJ wrote the manuscript.

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Correspondence to Shifeng **.

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Li, K., Tang, M., Tong, S. et al. BRAFi induced demethylation of miR-152-5p regulates phenotype switching by targeting TXNIP in cutaneous melanoma. Apoptosis 25, 179–191 (2020). https://doi.org/10.1007/s10495-019-01586-0

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