ArticleMolecular cancer2019
N-Myc promotes therapeutic resistance development of neuroendocrine prostate cancer by differentially regulating miR-421/ATM pathway.
Article in Molecular cancer, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 81 papers.
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81 citing papers in PubMed, 120 citations in OpenAlex.
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- A dual role of EZH2 in regulating A-to-I RNA editing and mRNA stability through ADAR.Nature communications · 2026Article
- Transcriptional and epigenetic reprogramming, lineage plasticity and therapy resistance in prostate cancer.Journal of the National Cancer Center · 2026Review
- A circulating microRNA-based diagnostic model for breast cancer, in which the miR-139-3p/RPA2 axis regulates the sensitivity to DNA-damaging agents.Translational cancer research · 2026Article
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- Targeting endoplasmic reticulum stress and nitroso-redox imbalance in neuroendocrine prostate cancer: the therapeutic role of nitric oxide.Cell death discovery · 2025Article
- AR to GR switch modulates differential TDO2-Kyn-AhR signalling to promote the survival and recurrence of treatment-induced dormant cells in prostate cancer.Cell discovery · 2025Article
- Myc family proteins: Molecular drivers of tumorigenesis and resistance in neuroendocrine tumors.Biochimica et biophysica acta. Reviews on cancer · 2025Review
- Genomic and transcriptomic landscapes of metastatic neuroendocrine neoplasms from distinct primary sites and their clinical implications.Scientific reports · 2025Article
- The role of transcription factors in prostate cancer progression.Molecules and cells · 2025Review
- Tuft cells transdifferentiate to neural-like progenitor cells in the progression of pancreatic cancer.Developmental cell · 2025Article
- LncRNA PCAT6 promotes progression and metastasis of colonic neuroendocrine carcinomaWorld journal of gastrointestinal oncology · 2025Article
- Spatially segregated APOETheranostics · 2025Article
- New Insights into Potential Therapeutic Targets for Neuroendocrine Prostate Cancer: From Bench to Clinic.Research (Washington, D.C.) · 2025Review
- Regulatory B cells promote the immunosuppressive microenvironment and progression of clear cell renal cell carcinoma.Immunotherapy advances · 2025Article
- Prognostic and immunological implications of cathepsin Z overexpression in prostate cancer.Frontiers in immunology · 2025Article
- New insights into markers for distinguishing neuroendocrine prostate cancer: evidence from single-cell analysis.Frontiers in immunology · 2025Article
21 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issued
Authors and funding
11 authors at 3 institutions in 2 countries.
Funding
Abstract
backgroundMYCN amplification or N-Myc overexpression is found in approximately 40% NEPC and up to 20% CRPC patients. N-Myc has been demonstrated to drive disease progression and hormonal therapeutic resistance of NEPC/CRPC. Here, we aim to identify the molecular mechanisms underlying the N-Myc-driven therapeutic resistance and provide new therapeutic targets for those N-Myc overexpressed NEPC/CRPC.
methodsN-Myc overexpressing stable cell lines for LNCaP and C4-2 were generated by lentivirus infection. ADT-induced senescence was measured by SA-β-gal staining in LNCaP cells in vitro and in LNCaP xenograft tumors in vivo. Migration, cell proliferation and colony formation assays were used to measure the cellular response after overexpressing N-Myc or perturbing the miR-421/ATM pathway. CRISPR-Cas9 was used to knock out ATM in C4-2 cells and MTS cell viability assay was used to evaluate the drug sensitivity of N-Myc overexpressing C4-2 cells in response to Enzalutamide and ATM inhibitor Ku60019 respectively or in combination.
resultsN-Myc overexpression suppressed ATM expression through upregulating miR-421 in LNCaP cells. This suppression alleviated the ADT-induced senescence in vitro and in vivo. Surprisingly, N-Myc overexpression upregulated ATM expression in C4-2 cells and this upregulation promoted migration and invasion of prostate cancer cells. Further, the N-Myc-induced ATM upregulation in C4-2 cells rendered the cells resistance to Enzalutamide, and inhibition of ATM by CRISPR-Cas9 knockout or ATM inhibitor Ku60019 re-sensitized them to Enzalutamide.
conclusionsN-Myc differentially regulating miR-421/ATM pathway contributes to ADT resistance and Enzalutamide resistance development respectively. Combination treatment with ATM inhibitor re-sensitizes N-Myc overexpressed CRPC cells to Enzalutamide. Our findings would offer a potential combination therapeutic strategy using ATM kinase inhibitor and Enzalutamide for the treatment of a subset of mCRPC with N-Myc overexpression that accounts for up to 20% CRPC patients.
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