دورية أكاديمية
Induction of DNMT3B by PGE2 and IL6 at Distant Metastatic Sites Promotes Epigenetic Modification and Breast Cancer Colonization
| العنوان: | Induction of DNMT3B by PGE2 and IL6 at Distant Metastatic Sites Promotes Epigenetic Modification and Breast Cancer Colonization |
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| المؤلفون: | So, Jae Young, Skrypek, Nicolas, Yang, Howard H, Merchant, Anand S, Nelson, George W, Chen, Wei-Dong, Ishii, Hiroki, Chen, Jennifer M, Hu, Gangqing, Achyut, Bhagelu R, Yoon, Esther C, Han, Liying, Huang, Chuanshu, Cam, Margaret C, Zhao, Keji, Lee, Maxwell P, Yang, Li |
| المصدر: | NYMC Faculty Publications |
| بيانات النشر: | Touro Scholar |
| سنة النشر: | 2020 |
| المجموعة: | Touro College & University System: Touro Scholar |
| مصطلحات موضوعية: | Animals, Antineoplastic Agents, Immunological, Antineoplastic Combined Chemotherapy Protocols, Breast, Breast Neoplasms, Cell Line, Tumor, Cyclooxygenase 2, Cyclooxygenase 2 Inhibitors, DNA (Cytosine-5-)-Methyltransferases, Datasets as Topic, Dinoprostone, Disease Models, Animal, Disease Progression, Epigenesis, Genetic, Female, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Humans, Interleukin-6, Lung Neoplasms, Mice, Programmed Cell Death 1 Receptor, Proof of Concept Study, Signal Transduction, Tumor Microenvironment |
| الوصف: | Current cancer treatments are largely based on the genetic characterization of primary tumors and are ineffective for metastatic disease. Here we report that DNA methyltransferase 3B (DNMT3B) is induced at distant metastatic sites and mediates epigenetic reprogramming of metastatic tumor cells. Multiomics analysis and spontaneous metastatic mouse models revealed that DNMT3B alters multiple pathways including STAT3, NFκB, PI3K/Akt, β-catenin, and Notch signaling, which are critical for cancer cell survival, apoptosis, proliferation, invasion, and colonization. PGE2 and IL6 were identified as critical inflammatory mediators in DNMT3B induction. DNMT3B expression levels positively correlated with human metastatic progression. Targeting IL6 or COX-2 reduced DNMT3B induction and improved chemo or PD1 therapy. We propose a novel mechanism linking the metastatic microenvironment with epigenetic alterations that occur at distant sites. These results caution against the "Achilles heel" in cancer therapies based on primary tumor characterization and suggests targeting DNMT3B induction as new option for treating metastatic disease. SIGNIFICANCE: These findings reveal that DNMT3B epigenetically regulates multiple pro-oncogenic signaling pathways via the inflammatory microenvironment at distant sites, cautioning the clinical approach basing current therapies on genetic characterization of primary tumors. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | unknown |
| العلاقة: | https://touroscholar.touro.edu/nymc_fac_pubs/3014Test |
| DOI: | 10.1158/0008-5472.CAN-19-3339 |
| الإتاحة: | https://doi.org/10.1158/0008-5472.CAN-19-3339Test https://touroscholar.touro.edu/nymc_fac_pubs/3014Test |
| رقم الانضمام: | edsbas.E9F81E94 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1158/0008-5472.CAN-19-3339 |
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