Table 1.
Overview of major epigenetic alterations induced by cytokines and associated with EMT and CSCs.
| Cytokine | Master TFs | Epigenetic Mechanism | Effect |
|---|---|---|---|
| TGFβ | Smads | Induction of Snail, Slug, and Zeb TFs up-regulates mesenchymal genes through reprogramming of specific chromatin domains (reduction of histone methylation by LSD1 and KDM6B/JMJD3 demethylases) | EMT and cancer progression |
| TGFβ | Smads | Snail- and Zeb-dependent down-regulation of miR-34 and miR-200 (double negative feedback loops) SIRT1-dependent miR-200 down-regulation by histone deacetylation (negative feedback loop) |
Induction of EMT and inhibition of MET |
| TGFβ | Various TFs | Several Smad-independent alterations, through MAPKs, PI-3K, and ΝF-κB pathways | EMT and cancer progression |
| TGFβ | Smad2/3–Smad4–Foxo | Reduced proliferation through induction of CDKN2B/p15ink4b, CDK4 inhibitor (removal of DNA methylation on CDKN2B promoter) | Tumor suppression |
| TNFα | NF-κB | Induction of ΝF-κB-regulated proteins (IL-6, IL-8, IL-18, iNOS, COX-2, 5-LOX, etc.) | Inflammation-dependent cancer development |
| TNFα | NF-κB | Induction of Twist1, Snail, Snail2, and Zebs leading to E-cadherin down-regulation and mesenchymal genes induction | EMT, migration and invasion |
| TNFα | NF-κB | DNMT1-dependent down-regulation of metastasis suppressor BRSM1 | Invasion and metastasis |
| TGFβ + TNFα | Smads + NF-κB |
Induction of EMT TFs leading to epigenetic alterations that induce mesenchymal genes and several oncomiRs (miR-21, miR-31, miR-23a, etc.) | EMT and cancer progression |
| IL-1 | NF-κB | Expression of several inflammatory mediators (including IL-1, leading to an autocrine loop) | Inflammation-dependent cancer development |
| IL-1α | NF-κB + STAT3 | Induction of stem-cell associated genes bmi-1 and Nestin | EMT and CSC development |
| IL-1β | β-catenin | Expression of c-MYC, CCDN1, Snail1 and MMP2, and BIRC3. Twist1-dependent methylation of ESR1 gene promoter |
EMT and cancer progression Resistance to chemotherapy |
| IL-1β | NF-κB | Induction of miR-181 or down-regulation of miR-506 | Cancer progression |
| IL-1β + TNFα + TGFβ | Several | Induction of inflammatory genes and several MMPs | EMT, migration and invasion |
| IL-6 | STAT3 | Induction of cell cycle regulators (E2Fs, JunB, c-Fos, etc.) and metabolic regulators (mTORC1) | Cancer progression |
| IL-6 | - | DNMT1 dependent DNA methylation of tumor suppressor gene promoters (CHFR, GATA5, and PAX6), including TP53 (negative feedback loop) | Cancer progression and CSC formation |
| IL-6 | ΝF-κB + STAT3 | Induction of EMT-TFs Snail, Slug, Twist, and Zeb (down-regulation of E-cadherin and up-regulation of mesenchymal genes and MMPs) | EMT, migration and invasion |
| IL-6 | ΝF-κB + STAT3 | Feedback loops involving IL-6, ΝF-κB, Lin28, and let-7 miRNA or IL-6, ΝF-κB, STAT3, miR-21 and miR-181b-1, and PTEN and CYLD | Cancer progression |