MiR-200a Regulates CDK4/6 Inhibitor Effect by Targeting CDK6 in Metastatic Melanoma.
The Journal of investigative dermatology
Biopsy, Needle; Cell Cycle; Cell Proliferation; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; DNA Methylation; Disease Progression; Down-Regulation; Epigenomics; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Melanoma; MicroRNAs; Neoplasm Metastasis; Sequence Analysis, RNA; Signal Transduction; Skin Neoplasms; Tumor Cells, Cultured
The CDK4/6 pathway is frequently dysregulated in cutaneous melanoma. Recently, CDK4/6 inhibitors have shown promising clinical activity against several cancer types, including melanoma. Here, we show that microRNA-200a decreases CDK6 expression and thus reduces the response of CDK4/6 inhibitor in highly proliferative metastatic melanoma. Down-regulation of microRNA-200a expression in melanoma cells is associated with disease progression and a higher number of lymph node metastases. Furthermore, microRNA-200a expression is epigenetically modulated by both DNA methylation at the promoter region and chromatin accessibility of an upstream genomic region with enhancer activity. Mechanistically, overexpression of miR-200a in metastatic melanoma cells induces cell cycle arrest by targeting CDK6 and decreases the levels of phosphorylated-Rb1 and E2F-downstream targets, diminishing cell proliferation; these effects are recovered by CDK6 overexpression. Conversely, low microRNA-200a expression in metastatic melanoma cells results in higher levels of CDK6 and a more significant response to CDK4/6 inhibitors. We propose that microRNA-200a functions as a "cell cycle brake" that is lost during melanoma progression to metastasis and provides the ability to identify melanomas that are highly proliferative and more prompted to respond to CDK4/6 inhibitors.
Bustos, Matias; Ono, Shigeshi; Marzese, Diego M; Oyama, Takashi; Iida, Yuuki; Cheung, Garrett; Nelson, Nellie; Hsu, Sandy C; Yu, Qiang; and Hoon, Dave S B, "MiR-200a Regulates CDK4/6 Inhibitor Effect by Targeting CDK6 in Metastatic Melanoma." (2017). Articles, Abstracts, and Reports. 1376.