Oncogenic Biogenesis of pri-miR-17∼92 Reveals Hierarchy and Competition among Polycistronic MicroRNAs

Abstract

The microRNAs encoded by the miR-17$92 polycistron are commonly overexpressed in cancer and orchestrate a wide range of oncogenic functions. Here, we identify a mechanism for miR-17$92 oncogenic function through the disruption of endogenous microRNA (miRNA) processing. We show that, upon oncogenic overexpression of the miR-17$92 primary transcript (pri-miR-17$92), the microprocessor complex remains associated with partially processed intermediates that aberrantly accumulate. These intermediates reflect a series of hierarchical and conserved steps in the early processing of the pri-miR-17$92 transcript. Encumbrance of the microprocessor by miR-17$92 intermediates leads to the broad but selective downregulation of co-expressed polycistronic miRNAs, including miRNAs derived from tumor-suppressive miR-34b/c and from the Dlk1-Dio3 polycistrons. We propose that the identified steps of polycistronic miR-17$92 biogenesis contribute to the oncogenic re-wiring of gene regulation networks. Our results reveal previously unappreciated functional paradigms for polycistronic miRNAs in cancer. 124 nt 82 nt 112 nt 79 nt 80 nt 56 nt 59 nt 63 nt 59nt 58 nt 61 nt 973 nt Hs miR-17-18a spacer 79 nt 80 nt 60 nt

miR-19 Promotes Cell Proliferation, Invasion, Migration, and EMT by Inhibiting SPRED2-mediated Autophagy in Osteosarcoma Cells

“…miR-19 is a member and the important oncogenic miRNA of miR-17-92 cluster, which is considered to be the first miRNA cluster with oncogenic potential [26][27][28] . So far, miR-19 has been proved to reduce apoptosis or chemosensitivity, and promote proliferation or migration in multiple cancers 29,30 .…”

The Evolution of Imprinted microRNAs and Their RNA Targets

“…Although a single miRNA can catalyze multiple rounds of mRNA cleavage [ 104 ], many regulatory interactions between targeted and targeting RNAs involve one-to-one sequestration of targets [ 105 , 106 , 107 , 108 ]. Dosage sensitivity is also expressed in competition among different pri-miRNAs for access to the machinery of miRNA-processing [ 109 ].…”

Functional Dissection of pri-miR-290~295 in Dgcr8 Knockout Mouse Embryonic Stem Cells

“…Few attentions have been paid on the function of pri- and pre-miRNA beyond miRNA production. However, several reports suggest that pri- and pre-miRNAs encode regulatory information and have a direct function in gene expression, chromatin interaction, and epigenetic state regulation [20,21,22,23]. Trujillo RD et al showed that pri-miR-let-7 might directly repress target mRNAs, and both loop structure and sequence elements of the pri-miRNA contributed to targeting binding and regulation [21].…”

“…Trujillo RD et al showed that pri-miR-let-7 might directly repress target mRNAs, and both loop structure and sequence elements of the pri-miRNA contributed to targeting binding and regulation [21]. A more recent study has identified partially processed RNA intermediates of pri-miR-17~92, which is amplified in numerous cancers and found to downregulate other co-expressed polycistronic miRNAs by competing for the Microprocessor [23]. In a mouse model of cardiac hypertrophy, pri-miR-208b could directly bind to polycomb group protein enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) and mediate the silencing of hypertrophic genes [22].…”

“…It is speculated that the interruption of the pri-miRNA processing may lead to the accumulation of large amounts of the primary transcripts in DGCR8 deficient cells. Although pri-miRNAs are considered transient intermediates during the production of mature miRNAs, several reports claimed that pri- and pre-miRNAs have direct regulatory functions in cognate RNA recognition and gene expression [20,21,22,23]. Whether the excessive pri-miRNA would disturb an elaborate regulatory network of gene expression and thereby contribute to the occurrence of abnormal cellular phenotype in Dgcr8 knockout cells has never been directly evaluated.…”