ArticleThe Journal of clinical investigation2023
ADORA2A-driven proline synthesis triggers epigenetic reprogramming in neuroendocrine prostate and lung cancers.
Article in The Journal of clinical investigation, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 28 citations in OpenAlex.
- Genes, fuel, and fate in lung cancer.Biochemical Society transactions · 2026Review
- PAX5 modulates vascularization and contributes to neuroendocrine lineage transition during carcinoma progression.The Journal of clinical investigation · 2026Article
- SPEN inactivation drives resistance to androgen receptor pathway inhibitors in metastatic prostate cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Article
- GPCR-Mediated Cell Intelligence: A Potential Mechanism for Survival and Long-Term Health.Current issues in molecular biology · 2026Review
- Dysregulated Proline Metabolism Exacerbates Hepatocellular Carcinoma Metastasis via EPRS1-Mediated mRNA Translation.Cancer communications (London, England) · 2026Article
- Identification and Validation of Alkaliptosis Resistance-Associated Genes in Prostate Cancer Via Transcriptome Sequencing and Prediction of Biochemical Recurrence.Molecular biotechnology · 2026Article
- Targeting RUNX1 Germline Variants: Agents Under Investigation.Current hematologic malignancy reports · 2025Review
- Targeting O-GlcNAcylation: Novel Therapeutic Strategies for Neurological Disease.Molecular neurobiology · 2025Review
- SIRT6 in Cancer: Mechanistic Insights into Its Dual Roles in Cancer Biology and Implications for Precision Therapeutic Development.Biomolecules · 2025Review
- Non-Canonical Functions of Adenosine Receptors: Emerging Roles in Metabolism, Immunometabolism, and Epigenetic Regulation.International journal of molecular sciences · 2025Review
- Metabolic reprogramming and therapeutic targeting in non-small cell lung cancer: emerging insights beyond the Warburg effect.Frontiers in oncology · 2025Review
- Molecular Sentinels: Unveiling the Role of Sirtuins in Prostate Cancer Progression.International journal of molecular sciences · 2024Review
- SIRT6 deficiency impairs the deacetylation and ubiquitination of UHRF1 to strengthen glycolysis and lactate secretion in bladder cancer.Cell & bioscience · 2024Article
- Brain Specific RagA Overexpression Triggers Depressive-Like Behaviors in Mice via Activating ADORA2A Signaling Pathway.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Study on the Chemical Composition and Anti-Tumor Mechanisms ofFoods (Basel, Switzerland) · 2024Article
- miR-5100 Overexpression Inhibits Prostate Cancer Progression by Inducing Cell Cycle Arrest and Targeting E2F7.Current issues in molecular biology · 2024Article
- Neuroendocrine transdifferentiation in human cancer: molecular mechanisms and therapeutic targets.MedComm · 2024Review
- Targeting SOX4/PCK2 signaling suppresses neuroendocrine trans-differentiation of castration-resistant prostate cancer.Biology direct · 2024Article
- Chromatin modifiers in human disease: from functional roles to regulatory mechanisms.Molecular biomedicine · 2024Review
- Correctly identifying the cells of origin is essential for tailoring treatment and understanding the emergence of cancer stem cells and late metastases.Frontiers in oncology · 2024Review
Corrections and comments
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Authors and funding
28 authors at 6 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Cell lineage plasticity is one of the major causes for the failure of targeted therapies in various cancers. However, the driver and actionable drug targets in promoting cancer cell lineage plasticity are scarcely identified. Here, we found that a G protein-coupled receptor, ADORA2A, is specifically upregulated during neuroendocrine differentiation, a common form of lineage plasticity in prostate cancer and lung cancer following targeted therapies. Activation of the ADORA2A signaling rewires the proline metabolism via an ERK/MYC/PYCR cascade. Increased proline synthesis promotes deacetylases SIRT6/7-mediated deacetylation of histone H3 at lysine 27 (H3K27), and thereby biases a global transcriptional output toward a neuroendocrine lineage profile. Ablation of Adora2a in genetically engineered mouse models inhibits the development and progression of neuroendocrine prostate and lung cancers, and, intriguingly, prevents the adenocarcinoma-to-neuroendocrine phenotypic transition. Importantly, pharmacological blockade of ADORA2A profoundly represses neuroendocrine prostate and lung cancer growth in vivo. Therefore, we believe that ADORA2A can be used as a promising therapeutic target to govern the epigenetic reprogramming in neuroendocrine malignancies.
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