MiR-200a Regulates CDK4/6 Inhibitor Effect by Targeting CDK6 in Metastatic Melanoma

The Journal of Investigative Dermatology
Matias A BustosDave S B Hoon

Abstract

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 ...Continue Reading

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Citations

Feb 6, 2020·International Journal of Molecular Sciences·Francesca Varrone, Emilia Caputo
May 11, 2021·Frontiers in Oncology·Soudeh Ghafouri-FardMohammad Taheri
Jun 12, 2018·Pharmacology & Therapeutics·Melina MitsiogianniMihalis I Panayiotidis
Aug 28, 2021·Cancers·Angeliki AndrikopoulouFlora Zagouri

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