ArticleCell death & disease2022
Induction of senescence-associated secretory phenotype underlies the therapeutic efficacy of PRC2 inhibition in cancer.
Article in Cell death & disease, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers, 1 of them a synthesis that pooled it.
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Who cites it
29 citing papers in PubMed, 1 synthesis or guideline pooled it, 37 citations in OpenAlex.
- Epigenetic regulation of major histocompatibility complexes in gastrointestinal malignancies and the potential for clinical interception.Clinical epigenetics · 2024Pooled it
- Cellular senescence and regulated cell death in cancer: mechanisms, cross-regulatory networks and therapeutic implications.Journal of hematology & oncology · 2026Review
- Integrated bioinformatic evaluation unveils a cellular senescence gene signature as a poor prognostic factor in hepatocellular carcinoma.Clinical and experimental medicine · 2026Article
- Systemic epigenetic dysregulation as a driver of ageing and a therapeutic target.Nature reviews. Molecular cell biology · 2026Review
- EZH2 Regulates the Proliferation-Senescence Balance and Tumor-Stromal Signaling in Lung Adenocarcinoma.International journal of molecular sciences · 2026Article
- Genotype-dependent metabolic and inflammatory regulation at the ANRIL locus in human primary macrophages.Molecular genetics and genomics : MGG · 2026Article
- Article
- Molecular and Biochemical Evidence of Edaravone's Impact on Dasatinib-induced AGS Cell Senescence: A Promising Strategy for Gastric Cancer Therapy.Current medicinal chemistry · 2026Article
- Immunoinflammation and post-translational modifications in the aging process.Journal of translational medicine · 2025Review
- Epigenetic Therapies in Endocrine-Related Cancers: Past Insights and Clinical Progress.Cancers · 2025Review
- BRAFiScience · 2025Article
- Unravelling Convergent Signaling Mechanisms Underlying the Aging-Disease Nexus Using Computational Language Analysis.Current issues in molecular biology · 2025Article
- Hypermethylation of CDKN2A CpG island drives resistance to PRC2 inhibitors in SWI/SNF loss-of-function tumors.Cell death & disease · 2024Article
- The role of the dynamic epigenetic landscape in senescence: orchestrating SASP expression.npj aging · 2024Review
- PPARγ and C/EBPα enable adipocyte differentiation upon inhibition of histone methyltransferase PRC2 in malignant tumors.The Journal of biological chemistry · 2024Article
- Targeting senescence-associated secretory phenotypes to remodel the tumour microenvironment and modulate tumour outcomes.Clinical and translational medicine · 2024Review
- The Wild West of spike-in normalization.Nature biotechnology · 2024Article
- The PRC2 complex epigenetically silences GATA4 to suppress cellular senescence and promote the progression of breast cancer.Translational oncology · 2024Article
- Epigenetic developmental mechanisms underlying sex differences in cancer.The Journal of clinical investigation · 2024Review
- BMP-ACVR1 Axis is Critical for Efficacy of PRC2 Inhibitors in B-Cell Lymphoma.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
Corrections and comments
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
Abstract
The methyltransferase Polycomb Repressive Complex 2 (PRC2), composed of EZH2, SUZ12, and EED subunits, is associated with transcriptional repression via tri-methylation of histone H3 on lysine 27 residue (H3K27me3). PRC2 is a valid drug target, as the EZH2 gain-of-function mutations identified in patient samples drive tumorigenesis. PRC2 inhibitors have been discovered and demonstrated anti-cancer efficacy in clinic. However, their pharmacological mechanisms are poorly understood. MAK683 is a potent EED inhibitor in clinical development. Focusing on MAK683-sensitive tumors with SMARCB1 or ARID1A loss, we identified a group of PRC2 target genes with high H3K27me3 signal through epigenomic and transcriptomic analysis. Multiple senescence-associated secretory phenotype (SASP) genes, such as GATA4, MMP2/10, ITGA2 and GBP1, are in this group besides previously identified CDKN2A/p16. Upon PRC2 inhibition, the de-repression of SASP genes is detected in multiple sensitive models and contributes to decreased Ki67+, extracellular matrix (ECM) reorganization, senescence associated inflammation and tumor regression even in CDKN2A/p16 knockout tumor. And the combination of PRC2 inhibitor and CDK4/6 inhibitor leads to better effect. The genes potential regulated by PRC2 in neuroblastoma samples exhibited significant enrichment of ECM and senescence associated inflammation, supporting the clinical relevance of our results. Altogether, our results unravel the pharmacological mechanism of PRC2 inhibitors and propose a combination strategy for MAK683 and other PRC2 drugs.
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