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

Matias Bustos, Division of Molecular Oncology, Department of Translational Molecular Medicine, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, California.Follow
Shigeshi Ono, Department of Translational Molecular Medicine, Division of Molecular Oncology, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, California, USA
Diego M Marzese, Department of Translational Molecular Medicine, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, USAFollow
Takashi Oyama, Department of Translational Molecular Medicine, Division of Molecular Oncology, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, California, USA
Yuuki Iida, Department of Translational Molecular Medicine, Division of Molecular Oncology, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, California, USA
Garrett Cheung, Department of Translational Molecular Medicine, Division of Molecular Oncology, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, California, USAFollow
Nellie Nelson, Sequencing Center, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, California, USA
Sandy C Hsu, Department of Translational Molecular Medicine, Division of Molecular Oncology, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, California, USA; Sequencing Center, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, California, USA
Qiang Yu
Dave S B Hoon, Department of Translational Molecular Medicine, John Wayne Cancer Institute (JWCI) at Providence Saint John's Health Center, Santa Monica, CA 90404 USA.Follow

Document Type

Article

Publication Date

9-1-2017

Publication Title

The Journal of investigative dermatology

Keywords

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

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 the ability to identify melanomas that are highly proliferative and more prompted to respond to CDK4/6 inhibitors.

Clinical Institute

Cancer

Department

Oncology

Department

Dermatology

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