DNMT1 Regulates Epithelial-Mesenchymal Transition and Cancer Stem Cells, Which Promotes Prostate Cancer Metastasis

Abstract

Cancer metastasis is a multistep process associated with the induction of an epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs). Although significant progress has been made in understanding the molecular mechanisms regulating EMT and the CSC phenotype, little is known of how these processes are regulated by epigenetics. Here we demonstrate that reduced expression of DNA methyltransferase 1 (DNMT1) plays an important role in the induction of EMT and the CSC phenotype by prostate cancer (PCa) cells, with enhanced tumorigenesis and metastasis. First, we observed that reduction of DNMT1 by 5-azacitidine (5-Aza) promotes EMT induction as well as CSCs and sphere formation in vitro. Reduced expression of DNMT1 significantly increased PCa migratory potential. We showed that the increase of EMT and CSC activities by reduction of DNMT1 is associated with the increase of protein kinase C. Furthermore, we confirmed that silencing DNMT1 is correlated with enhancement of the induction of EMT and the CSC phenotype in PCa cells. Additionally, chromatin immunoprecipitation assay reveals that reduction of DNMT1 promotes the suppression of H3K9me3 and H3K27me3 on the Zeb2 and KLF4 promoter region in PCa cells. Critically, we found in an animal model that significant tumor growth and more disseminated tumor cells in most osseous tissues were observed following injection of 5-Aza pretreated–PCa cells compared with vehicle-pretreated PCa cells. Our results suggest that epigenetic alteration of histone demethylation regulated by reduction of DNMT1 may control induction of EMT and the CSC phenotype, which facilitates tumorigenesis in PCa cells and has important therapeutic implications in targeting epigenetic regulation.

The evolving concept of cancer stem-like cells in thyroid cancer and other solid tumors

“…13,32,55 Phenotypic plasticity may allow non-CSCs to acquire CSC traits and replenish the CSC pool as has been reported in malignancies such as malignant melanomas 56,57 and prostate cancers. 58 Roesch et al 57 used the H3K4 demethylase JARID1B as a biomarker and characterized a small subpopulation of slow-cycling melanoma cells that cycled with doubling times of 44 weeks within the rapidly proliferating main population. Isolated JARID1B-positive melanoma cells gave rise to highly proliferative progeny.…”

“…Knockdown of JARID1B led to an initial acceleration of tumor growth followed by exhaustion, which suggested that JARID1B-positive sub-population was essential for continuous growth. Lee et al 58 reported that reduced expression of DNA methyltransferase 1 (DNMT1) had an important role in the induction of EMT and CSC phenotype in prostate cancer cells. After reducing DNMT1 by 5-azacytidine, there was promotion of EMT induction, as well as CSC sphere formation.…”

MiR-137 Suppresses Triple-Negative Breast Cancer Stemness and Tumorigenesis by Perturbing BCL11A-DNMT1 Interaction

“…Previous studies have demonstrated that DNMT1 is required for maintenance of CSC in a variety of cancers, including prostate cancer, pancreatic cancer and breast cancer [22][23][24]. For instance, DNMT1 induces histone demethylation of H3K9me3 and H3K27me3 on the Zeb2 and KLF4 promoter in prostate cancer cells [23].…”

Prostate Cancer Stem Cells and Nanotechnology: A Focus on Wnt Signaling

“…Prostate cancer stem cells can also be derived from reprograming of differentiated cells via epithelial-mesenchymal transition (EMT), in which epithelial cells lose their polarity and cell–cell adhesion and gain migratory and invasive properties of mesenchymal cells (Kong et al, 2010; Talati et al, 2015; Lee et al, 2016). Kong et al (2010) reported that overexpression of platelet-derived growth factor D (PDGFD) resulted in the loss of epithelial markers and increasing mesenchymal markers in prostate cancer cells.…”

“…Suppressing DNA methyltransferase 1 (DNMT1) by 5-azacitidine (5-Aza) in prostate cancer cells can also induce EMT and stimulate transition of PCSCs. 5-Aza treated prostate cancer cells showed enhanced CD133 + CD44 + phenotype and prostasphere formation ability, and elevated expression of stem cell-related transcription factors KLF4 and Sox2 (Lee et al, 2016). Activation of Jak2-Stat5a/b signaling promotes metastasis by inducing EMT and stem cell properties in prostate cancer cells, as shown by sphere formation and expression of CSC markers BMI-1, CD44, and Sox2 (Talati et al, 2015).…”