DLEU2, frequently deleted in malignancy, functions as a critical host gene of the cell cycle inhibitory microRNAs miR-15a and miR-16-1.
The microRNAs miR-15a and miR-16-1 are downregulated in multiple tumor types and are frequently deleted in chronic lymphocytic leukemia (CLL), myeloma and mantle cell lymphoma. Despite their abundance in most cells the transcriptional regulation of miR-15a/16-1 remains unclear. Here we demonstrate that the putative tumor suppressor DLEU2 acts as a host gene of these microRNAs. Mature miR-15a/miR-16-1 are produced in a Drosha-dependent process from DLEU2 and binding of the Myc oncoprotein to two alterative DLEU2 promoters represses both the host gene transcript and levels of mature miR-15a/miR-16-1. In line with a functional role for DLEU2 in the expression of the microRNAs, the miR-15a/miR-16-1 locus is retained in four CLL cases that delete both promoters of this gene and expression analysis indicates that this leads to functional loss of mature miR-15a/16-1. We additionally show that DLEU2 negatively regulates the G1 Cyclins E1 and D1 through miR-15a/miR-16-1 and provide evidence that these oncoproteins are subject to miR-15a/miR-16-1-mediated repression under normal conditions. We also demonstrate that DLEU2 overexpression blocks cellular proliferation and inhibits the colony-forming ability of tumor cell lines in a miR-15a/miR-16-1-dependent way. Together the data illuminate how inactivation of DLEU2 promotes cell proliferation and tumor progression through functional loss of miR-15a/miR-16-1.
Lerner
Mikael
M
Department of Oncology-Pathology, Cancercentrum Karolinska, Karolinska Institutet R8:03, 171 76 Stockholm, Sweden.
Harada
Masako
M
Lovén
Jakob
J
Castro
Juan
J
Davis
Zadie
Z
Oscier
David
D
Henriksson
Marie
M
Sangfelt
Olle
O
Grandér
Dan
D
Corcoran
Martin M
MM
D001853:Bone Marrow / Q000502:physiology; D002453:Cell Cycle / Q000235:genetics*; D002460:Cell Line; D002843:Chromatin / Q000235:genetics; D003114:Colony-Forming Units Assay; D019938:Cyclin D1 / Q000235:genetics; D019927:Cyclin E / Q000235:genetics; D016213:Cyclins / Q000235:genetics; D004247:DNA / Q000235:genetics; D017931:DNA Primers; D005434:Flow Cytometry; D017353:Gene Deletion; D006801:Humans; D007668:Kidney / Q000196:embryology; D035683:MicroRNAs / Q000235:genetics* / Q000502:physiology; D009369:Neoplasms / Q000235:genetics*; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics; D062085:RNA, Long Noncoding; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014166:Transferases; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000235:genetics*
D002843:Chromatin; D019927:Cyclin E; D016213:Cyclins; C109420:DLEU2 lncRNA, human; D017931:DNA Primers; D035683:MicroRNAs; D062085:RNA, Long Noncoding; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; D012313:RNA; D004247:DNA; D014166:Transferases