Krüppel-like factor 4 (KLF4) regulates the miR-183~96~182 cluster under physiologic and pathologic conditions
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Miguel F. Segura1,2,3, Luz Jubierre3, SiDe Li4, Aroa Soriano3, Lisa Koetz1,2, Avital Gaziel-Sovran1,2, Marc Masanas3, Kevin Kleffman1,2, John F. Dankert1,2, Martin J Walsh4, Eva Hernando1,2
1Department of Pathology, New York University School of Medicine, New York, NY, USA
2Interdisciplinary Melanoma Cooperative Group, New York University Perlmutter Cancer Institute, NYU School of Medicine, New York, NY, USA
3Laboratory of Translational Research in Child and Adolescent Cancer, Vall d'Hebron Research Institute (VHIR)-UAB, Barcelona, Spain
4Departments of Structural and Chemical Biology, Genetics and Genomic Sciences and Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Miguel F. Segura, email: email@example.com
Eva Hernando, email: firstname.lastname@example.org
Keywords: microRNA, embryonic stem cells, melanoma, miR-183~96~182 cluster, KLF4
Received: June 30, 2016 Accepted: February 06, 2017 Published: February 17, 2017
MicroRNAs (miRNAs) are a class of endogenous non-coding small RNAs that post-transcriptionally control the translation and stability of target mRNAs in a sequence-dependent manner. MiRNAs are essential for key cellular processes including proliferation, differentiation, cell death and metabolism, among others. Consequently, alterations of miRNA expression contribute to developmental defects and a myriad of diseases.
The expression of miRNAs can be altered by several mechanisms including gene copy number alterations, aberrant DNA methylation, defects of the miRNA processing machinery or unscheduled expression of transcription factors. In this work, we sought to analyze the regulation of the miR-182 cluster, located at the 7q32 locus, which encodes three different miRNAs that are abundantly expressed in human embryonic stem cells and de-regulated in cancer. We have found that the Krüppel-like factor 4 (KLF4) directly regulates miR-182 cluster expression in human embryonic stem cells (hESCs) and in melanoma tumors, in which the miR-182 cluster is highly expressed and has a pro-metastatic role. Furthermore, higher KLF4 expression was found to be associated with metastatic progression and poor patient outcome. Loss of function experiments revealed that KLF4 is required for melanoma cell maintenance. These findings provide new insights into the regulation of the miR-182 cluster expression and new opportunities for therapeutic intervention in tumors in which the KLF4-miR-182 cluster axis is deregulated.
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