ArticleProceedings of the National Academy of Sciences of the United States of America2022
Inhibition of EZH2 transactivation function sensitizes solid tumors to genotoxic stress.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 53 citations in OpenAlex.
- NRF1 predominantly causes EZH2 overexpression in cancer cells.Cell death & disease · 2026Article
- Genomic and Immune Correlates of EZH2 Expression and Activity in Olfactory Neuroblastoma.Head & neck · 2026Article
- A dual role of EZH2 in regulating A-to-I RNA editing and mRNA stability through ADAR.Nature communications · 2026Article
- BARTsc identifies key transcriptional regulators from single-cell omics data.bioRxiv : the preprint server for biology · 2026Article
- Article
- EZH2 crosstalk with RNA methylation promotes prostate cancer progression through modulation of m6A autoregulation pathway.The Journal of clinical investigation · 2026Article
- Cancer suppresses mitochondrial chaperone activity in macrophages to drive immune evasion.Nature immunology · 2025Article
- Upregulation of YY1/EZH2 and MLH1 as Therapeutic Targets for Adult T-Cell Leukemia/Lymphoma.Cancer science · 2025Article
- Integrative multi-omics identifies AP-1 transcription factor as a targetable mediator of acquired osimertinib resistance in non-small cell lung cancer.Cell death & disease · 2025Article
- Multiplex gene editing models of del(7q) reveal combinedBlood neoplasia · 2025Article
- EZH2-Mediated PHF10 Suppression Amplifies HMGB1/NF-κB Axis That Confers Chemotherapy Resistance in Cholangiocarcinoma.Journal of cellular and molecular medicine · 2025Article
- Exploring oncogenic roles and clinical significance of EZH2: focus on non-canonical activities.Therapeutic advances in medical oncology · 2025Review
- The Role of EZH2 in Initiating Epigenetic Regulation of CRSwNP.Journal of inflammation research · 2025Article
- Phosphorylation-mediated disassembly of C-terminal binding protein 2 tetramer impedes epigenetic silencing of pluripotency in mouse embryonic stem cells.Nucleic acids research · 2024Article
- EZH2 directly methylates PARP1 and regulates its activity in cancer.Science advances · 2024Article
- Functional inversion of circadian regulator REV-ERBα leads to tumorigenic gene reprogramming.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Lineage-specific canonical and non-canonical activity of EZH2 in advanced prostate cancer subtypes.Nature communications · 2024Article
- Comprehensive Target Engagement by the EZH2 Inhibitor Tulmimetostat Allows for Targeting of ARID1A Mutant Cancers.Cancer research · 2024Article
- Discovery of a peptide proteolysis-targeting chimera (PROTAC) drug of p300 for prostate cancer therapy.EBioMedicine · 2024Article
- Splicing targeting drugs highlight intron retention as an actionable vulnerability in advanced prostate cancer.Journal of experimental & clinical cancer research : CR · 2024Article
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Authors and funding
30 authors at 6 institutions in 1 country.
Funding
Abstract
Drugs that block the activity of the methyltransferase EZH2 are in clinical development for the treatment of non-Hodgkin lymphomas harboring EZH2 gain-of-function mutations that enhance its polycomb repressive function. We have previously reported that EZH2 can act as a transcriptional activator in castration-resistant prostate cancer (CRPC). Now we show that EZH2 inhibitors can also block the transactivation activity of EZH2 and inhibit the growth of CRPC cells. Gene expression and epigenomics profiling of cells treated with EZH2 inhibitors demonstrated that in addition to derepressing gene expression, these compounds also robustly down-regulate a set of DNA damage repair (DDR) genes, especially those involved in the base excision repair (BER) pathway. Methylation of the pioneer factor FOXA1 by EZH2 contributes to the activation of these genes, and interaction with the transcriptional coactivator P300 via the transactivation domain on EZH2 directly turns on the transcription. In addition, CRISPR-Cas9-mediated knockout screens in the presence of EZH2 inhibitors identified these BER genes as the determinants that underlie the growth-inhibitory effect of EZH2 inhibitors. Interrogation of public data from diverse types of solid tumors expressing wild-type EZH2 demonstrated that expression of DDR genes is significantly correlated with EZH2 dependency and cellular sensitivity to EZH2 inhibitors. Consistent with these findings, treatment of CRPC cells with EZH2 inhibitors dramatically enhances their sensitivity to genotoxic stress. These studies reveal a previously unappreciated mechanism of action of EZH2 inhibitors and provide a mechanistic basis for potential combination cancer therapies.
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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.