Induction of DNMT3B by PGE2 and IL6 at Distant Metastatic Sites Promotes Epigenetic Modification and Breast Cancer Colonization
- 6 April 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 80 (12), 2612-2627
- https://doi.org/10.1158/0008-5472.CAN-19-3339
Abstract
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, NFkB, PI3K/Akt, beta-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.Other Versions
Funding Information
- NCI (SMAD2, SMAD3)
This publication has 53 references indexed in Scilit:
- Aberrant Overexpression of IL-15 Initiates Large Granular Lymphocyte Leukemia through Chromosomal Instability and DNA HypermethylationCancer Cell, 2012
- Functions of DNA methylation: islands, start sites, gene bodies and beyondNature Reviews Genetics, 2012
- DNA Methylation Screening Identifies Driver Epigenetic Events of Cancer Cell SurvivalCancer Cell, 2012
- Prostaglandin E2 promotes intestinal tumor growth via DNA methylationNature Medicine, 2012
- CD31, EDNRB and TSPAN7 are promising prognostic markers in clear‐cell renal cell carcinoma revealed by genome‐wide expression analyses of primary tumors and metastasesInternational Journal of Cancer, 2011
- Oxidative Damage Targets Complexes Containing DNA Methyltransferases, SIRT1, and Polycomb Members to Promoter CpG IslandsCancer Cell, 2011
- Eicosanoids and cancerNature Reviews Cancer, 2010
- Myeloid-derived suppressor cells as regulators of the immune systemNature Reviews Immunology, 2009
- The Epigenomics of CancerCell, 2007
- DNMT1 and DNMT3b cooperate to silence genes in human cancer cellsNature, 2002