ArticleCancer science2019
Akt inhibition synergizes with polycomb repressive complex 2 inhibition in the treatment of multiple myeloma.
Article in Cancer science, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 24 citations in OpenAlex.
- Massive deciphering of the tissue nucleic acid-binding proteome via affinity chromatography integrated with data-independent acquisition-based proteomics.Nucleic acids research · 2025Article
- FoxO1 signaling in B cell malignancies and its therapeutic targeting.FEBS letters · 2025Review
- Pharmacological Advancements of PRC2 in Cancer Therapy: A Narrative Review.Life (Basel, Switzerland) · 2024Review
- MEK/ERK and PI3K/AKT pathway inhibitors affect the transformation of myelodysplastic syndrome into acute myeloid leukemia via H3K27me3 methylases and de‑methylases.International journal of oncology · 2023Article
- The roles of EZH2 in cancer and its inhibitors.Medical oncology (Northwood, London, England) · 2023Review
- The discrete roles of individual FOXO transcription factor family members in B-cell malignancies.Frontiers in immunology · 2023Review
- Insights into high-risk multiple myeloma from an analysis of the role of PHF19 in cancer.Journal of experimental & clinical cancer research : CR · 2021Review
- One Omics Approach Does Not Rule Them All: The Metabolome and the Epigenome Join Forces in Haematological Malignancies.Epigenomes · 2021Review
- The combination of the tubulin binding small molecule PTC596 and proteasome inhibitors suppresses the growth of myeloma cells.Scientific reports · 2021Article
- Downregulation of ATXN3 Enhances the Sensitivity to AKT Inhibitors (Perifosine or MK-2206), but Decreases the Sensitivity to Chemotherapeutic Drugs (Etoposide or Cisplatin) in Neuroblastoma Cells.Frontiers in oncology · 2021Article
- MicroRNA-20a Suppresses Tumor Proliferation and Metastasis in Hepatocellular Carcinoma by Directly Targeting EZH1.Frontiers in oncology · 2021Article
- Pathogenic Impacts of Dysregulated Polycomb Repressive Complex Function in Hematological Malignancies.International journal of molecular sciences · 2020Review
- Role of Polycomb Complexes in Normal and Malignant Plasma Cells.International journal of molecular sciences · 2020Review
- Expression of L-type amino acid transporter 1 as a molecular target for prognostic and therapeutic indicators in bladder carcinoma.Scientific reports · 2020Article
- Akt inhibition synergizes with polycomb repressive complex 2 inhibition in the treatment of multiple myeloma.Cancer science · 2019Article
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Authors and funding
13 authors at 4 institutions in 2 countries.
Funding
Abstract
Polycomb repressive complex 2 (PRC2) components, EZH2 and its homolog EZH1, and PI3K/Akt signaling pathway are focal points as therapeutic targets for multiple myeloma. However, the exact crosstalk between their downstream targets remains unclear. We herein elucidated some epigenetic interactions following Akt inhibition and demonstrated the efficacy of the combined inhibition of Akt and PRC2. We found that TAS-117, a potent and selective Akt inhibitor, downregulated EZH2 expression at the mRNA and protein levels via interference with the Rb-E2F pathway, while EZH1 was compensatively upregulated to maintain H3K27me3 modifications. Consistent with these results, the dual EZH2/EZH1 inhibitor, UNC1999, but not the selective EZH2 inhibitor, GSK126, synergistically enhanced TAS-117-induced cytotoxicity and provoked myeloma cell apoptosis. RNA-seq analysis revealed the activation of the FOXO signaling pathway after TAS-117 treatment. FOXO3/4 mRNA and their downstream targets were upregulated with the enhanced nuclear localization of FOXO3 protein after TAS-117 treatment. ChIP assays confirmed the direct binding of FOXO3 to EZH1 promoter, which was enhanced by TAS-117 treatment. Moreover, FOXO3 knockdown repressed EZH1 expression. Collectively, the present results reveal some molecular interactions between Akt signaling and epigenetic modulators, which emphasize the benefits of targeting PRC2 full activity and the Akt pathway as a therapeutic option for multiple myeloma.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.