In the human brain, microRNAs (miRNAs) from the microRNA-376 (miR-376) cluster undergo programmed "seed" sequence modifications by adenosine-to-inosine (A-to-I) editing. Emerging evidence suggests a link between impaired A-to-I editing and cancer, particularly in high-grade gliomas. We hypothesized that disruption of A-to-I editing alters expression of genes regulating glioma tumor phenotypes. By sequencing the miR-376 cluster, we show that the overall miRNA editing frequencies were reduced in human gliomas. Specifically in high-grade gliomas, miR-376a* accumulated entirely in an unedited form. Clinically, a significant correlation was found between accumulation of unedited miR-376a* and the extent of invasive tumor spread as measured by magnetic resonance imaging of patient brains. Using both in vitro and orthotopic xenograft mouse models, we demonstrated that the unedited miR-376a* promoted glioma cell migration and invasion, while the edited miR-376a* suppressed these features. The effects of the unedited miR-376a* were mediated by its sequence-dependent ability to target RAP2A and concomitant inability to target AMFR. Thus, the tumordependent introduction of a single base difference in the miR-376a* sequence dramatically alters the selection of its target genes and redirects its function from inhibiting to promoting glioma cell invasion. These findings uncover a new mechanism of miRNA deregulation and identify unedited miR-376a* as a potential therapeutic target in glioblastoma cells. IntroductionMicroRNAs (miRNAs) are short, noncoding RNAs that mediate post-transcriptional silencing of a set of target genes. The target gene specificity of each miRNA is dictated by sequence-dependent interaction between approximately 22-nt-long mature miRNAs, especially their 6-or 7-nucleotide "seed" sequences at the 5′ end, and the 3′ untranslated regions of mRNAs (1). It has been shown that the epigenetic process of adenosineto-inosine (A-to-I) editing of certain miRNAs can lead to a single base substitution in their seed sequence and generate variant "edited" mature miRNA species with target gene specificity drastically different from that of the unedited, genomically encoded miRNA (2). This was demonstrated for miR-376 cluster transcripts collected from normal human and mouse tissues. The miR-376 cluster encodes 4 primary miRNAs (primiRs), including pri-miR-376a1, -376a2, -376b, and -376c, that are processed to 5 distinct mature miRNAs, miR-376a, -376a*, -376a2-5p, -376b, and -376c. In the human brain, 9 adenosines within this miRNA cluster are subject to specific and high-level A-to-I RNA editing (2).In gliomas, the most frequent primary brain tumors, Alu repeats and several protein-coding substrates of adenosine deaminases acting on RNA (ADARs; a family of enzymes that mediate A-to-I editing of RNAs) have been found to be edited to lower than normal frequencies (3-5). Particularly in high-grade gliomas, glioblastoma multiforme (GBMs), emerging lines of evidence suggest a
Competitive BET bromodomain inhibitors (BBIs) targeting BET proteins (BRD2, BRD3, BRD4, and BRDT) show promising preclinical activities against brain cancers. However, the BET protein-dependent glioblastoma (GBM)-promoting transcriptional network remains elusive. Here, with mechanistic exploration of a next-generation chemical degrader of BET proteins (dBET6), we reveal a profound and consistent impact of BET proteins on E2F1- dependent transcriptional program in both differentiated GBM cells and brain tumor-initiating cells. dBET6 treatment drastically reduces BET protein genomic occupancy, RNA-Pol2 activity, and permissive chromatin marks. Subsequently, dBET6 represses the proliferation, self-renewal, and tumorigenic ability of GBM cells. Moreover, dBET6-induced degradation of BET proteins exerts superior antiproliferation effects compared to conventional BBIs and overcomes both intrinsic and acquired resistance to BBIs in GBM cells. Our study reveals crucial functions of BET proteins and provides the rationale and therapeutic merits of targeted degradation of BET proteins in GBM.
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