ArticleBMC cancer2024
The BET PROTAC inhibitor GNE-987 displays anti-tumor effects by targeting super-enhancers regulated gene in osteosarcoma.
Article in BMC cancer, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed.
- Harnessing MDM2-Mediated Targeted Degradation of Transcriptional and Epigenetic Machinery to Disrupt Oncogenic Addictions in Pediatric Sarcoma.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Acetylation in ovarian cancer: mechanistic insights into drug resistance and emerging therapeutic opportunities.Journal of ovarian research · 2026Review
- BRD4 regulation of PIM1 identifies a novel therapeutic vulnerability in acute megakaryoblastic leukemia.Cancer cell international · 2026Article
- SETD2 methyltransferase activity promotes correct transcription initiation and termination.EMBO reports · 2026Article
- Mechanistic role of GNE-987 targeting BRD4-HCP5 axis in pediatric T-cell acute lymphoblastic leukemia.Journal of cell communication and signaling · 2026Article
- Design of Tissue-Selective PROTACs Through Recruiting E3 Ligase Scaffolding Protein MAGEA11.bioRxiv : the preprint server for biology · 2025Article
- Review
- Targeting developmental vulnerabilities in childhood sarcomas.Cancer metastasis reviews · 2025Review
- Super-enhancers in immune system regulation: mechanisms, pathological reprogramming, and therapeutic opportunities.Frontiers in immunology · 2025Review
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Authors and funding
15 authors.
Funding
Abstract
backgroundOsteosarcoma (OS) is one of the most common primary malignant tumors of bone in children, which develops from osteoblasts and typically occurs during the rapid growth phase of the bone. Recently, Super-Enhancers(SEs)have been reported to play a crucial role in osteosarcoma growth and metastasis. Therefore, there is an urgent need to identify specific targeted inhibitors of SEs to assist clinical therapy. This study aimed to elucidate the role of BRD4 inhibitor GNE-987 targeting SEs in OS and preliminarily explore its mechanism.
methodsWe evaluated changes in osteosarcoma cells following treatment with a BRD4 inhibitor GNE-987. We assessed the anti-tumor effect of GNE-987 in vitro and in vivo by Western blot, CCK8, flow cytometry detection, clone formation, xenograft tumor size measurements, and Ki67 immunohistochemical staining, and combined ChIP-seq with RNA-seq techniques to find its anti-tumor mechanism.
resultsIn this study, we found that extremely low concentrations of GNE-987(2-10 nM) significantly reduced the proliferation and survival of OS cells by degrading BRD4. In addition, we found that GNE-987 markedly induced cell cycle arrest and apoptosis in OS cells. Further study indicated that VHL was critical for GNE-987 to exert its antitumor effect in OS cells. Consistent with in vitro results, GNE-987 administration significantly reduced tumor size in xenograft models with minimal toxicity, and partially degraded the BRD4 protein. KRT80 was identified through analysis of the RNA-seq and ChIP-seq data. U2OS HiC analysis suggested a higher frequency of chromatin interactions near the KRT80 binding site. The enrichment of H3K27ac modification at KRT80 was significantly reduced after GNE-987 treatment. KRT80 was identified as playing an important role in OS occurrence and development.
conclusionsThis research revealed that GNE-987 selectively degraded BRD4 and disrupted the transcriptional regulation of oncogenes in OS. GNE-987 has the potential to affect KRT80 against OS.
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