Table 2.
Influence of histone deacetylase inhibitors (HDIs) on epithelial-mesenchymal transition (EMT) markers, transcription factors, morphology, migration and invasion of cancer cells in vitro and in vivo.
| Type of Cancer | HDI (Individually or in Combination) | Experimental Model | Type of Treatment | E-cadherin | B-catenin | N-cadherin | Vimentin | Transcription Factors | Changes in Morphology | Migration and Invasion | Ref. |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Lung cancer | SAHA | A549 cells in vitro | cells treated with SAHA vs. untreated cells | ↓ | → | N/A | ↑ | ↑SLUG | from cobblestone to mesenchymal spindle-like | ↑migration | [118] |
| Lung cancer | TSA | A549 cells in vitro | irradiated cells treated with TSA vs. irradiated cells | ↑ | ↑ | ↓ | ↓ | ↓SNAIL, ZEB | reduction of mesenchymal-like phenotype | ↓migration | [114] [115] |
| Lung cancer | TSA + silibinin | H1299 cells in vitro | cells treated with TSA and silibinin vs. cells treated with silibinin | ↑ | N/A | N/A | N/A | ↓ZEB1 | N/A | ↓migration and invasion | [116] |
| Lung cancer | VPA | A549 cells in vitro | cells treated with VPA vs. untreated cells | ↑ | N/A | N/A | N/A | N/A | reduction of spindle-like morphology | N/A | [117] |
| Hepatocellular carcinoma | TSA | HepG2 cells, Huh7 cells in vitro | cells treated with TSA vs. untreated cells | ↓ | N/A | ↑ | ↑ | ↑SNAIL, TWIST | N/A | ↑migration and invasion | [120] |
| Hepatocellular carcinoma | VPA | HepG2 cells, Huh7 cells in vitro | cells treated with VPA vs. untreated cells | ↓ | N/A | ↑ | ↑ | ↑SNAIL, TWIST | N/A | ↑migration and invasion | [120] |
| Hepatocellular carcinoma | SAHA | HepG2 cells in vitro | cells treated with SAHA vs. untreated cells | ↓ | N/A | ↑ | ↑ | ↑SNAIL, TWIST | N/A | ↑migration and invasion | [120] |
| Hepatocellular carcinoma | MS-275 | HepG2 cells in vitro | cells treated with MS-275 vs. untreated cells | ↓ | N/A | ↑ | ↑ | ↑SNAIL, TWIST | N/A | ↑migration and invasion | [120] |
| Hepatocellular carcinoma | SAHA | HepG2 cells, QGY-7703 cells in vitro; mouse in vivo | cells treated with SAHA vs. untreated cells | N/A | N/A | ↑ | ↑ | ↑SNAIL through SMAD2/3 phosphorylation |
changes of phenotype were detected | ↑invasion | [121] |
| Hepatocellular carcinoma | NaB | HepG2 cells/QGY-7703 cells in vitro; mouse in vivo | cells treated with NaB vs. untreated cells | N/A | N/A | N/A | ↑ | ↑SNAIL through SMAD2/3 phosphorylation | N/A | ↑invasion | [121] |
| Hepatocellular carcinoma | LBH589 | HepG2 cells in vitro | cells treated with LBH589 vs. untreated cells | ↑ | N/A | ↓ | ↓ | ↓TWIST1 | N/A | ↓invasion | [122] |
| Hepatocellular carcinoma | RAS2410 | Hep3B, HLE, HLF cells in vitro | cells treated with RAS2410 vs. untreated cells | ↑ | N/A | ↓ | ↓ | →TWIST, SNAI1 | N/A | ↓migration and invasion | [123] |
| Cholangiocarcinoma | VPA | HuCC-T1 cells in vitro | cells treated with VPA vs. untreated cells | → | N/A | N/A | → | N/A | no changes | ↓migration and invasion | [124] |
| Cholangiocarcinoma | TSA | HuCC-T1 cells in vitro | cells treated with TSA vs. untreated cells | ↑ | N/A | N/A | ↑ | N/A | no changes | ↓migration and invasion | [124] |
| Cholangiocarcinoma | VPA + gemcitabine | HuCC-T1 cells in vitro | cells treated with VPA and gemcitabine vs. cells treated gemcitabine | ↑ | N/A | N/A | ↑ | N/A | from spindle to rectangular caused by gemcitabine | ↓migration and invasion | [124] |
| Cholangiocarcinoma | TSA + gemcitabine | HuCC-T1 cells in vitro | cells treated with TSA and gemcitabine vs. cells treated gemcitabine | ↑ | N/A | N/A | ↑ | N/A | from spindle to rectangular caused by gemcitabine | ↓migration and invasion | [124] |
| Pancreatic cancer | 4SC-202 | Panc1 cells L3.6 cells in vitro | TGF-β1 pretreated Panc1 cells treated with 4SC-202 vs. untreated cells in vitro; mice with implanted L3.6 cells in vivo | ↓ | N/A | ↑ | ↓ | ↓ZEB1, SNAIL1 | N/A | N/A | [125] |
| Pancreatic cancer | BSI | Panc1 cells in vitro | Panc1 cells treated with BSI vs. untreated cells in vitro | ↑ | N/A | ↓ | N/A | ↓SNAIL | tumor spheres formation is unchanged but their size is significantly decreased | ↓migration and invasion | [126] |
| Pancreatic cancer | MGCD103 + gemcitabine | Panc1 cells, hPaca-1 derived tumor cells in vitro | Panc1 cells, hPaca-1 derived tumor cells treated with MGCD103 and gemcitabine vs. gemcitabine treated cells in vitro | ↑ | N/A | N/A | N/A | ↓ZEB1 | N/A | N/A | [127] |
| Pancreatic cancer | SAHA | Pancreatic CSCs | pancreatic CSCs treated with SAHA vs. untreated cells in vitro | ↑ | N/A | ↓ | N/A | ↓ZEB, SNAIL, SLUG | N/A | ↓invasion | [12] |
| Colorectal cancer | TSA | SW480 cells in vitro | cells treated with TSA vs. untreated cells | ↑ | N/A | N/A | ↓ | ↓SLUG | N/A | ↓migration and invasion | [121] |
| Colorectal cancer | VPA | SW480 cells in vitro | cells treated with VPA vs. untreated cells | ↓ | N/A | ↑ | ↑ | ↑SNAIL | N/A | ↑migration and invasion | [128] |
| Colorectal cancer | VPA | HCT116 cells in vitro | cells treated with VPA vs. untreated cells | ↓ | N/A | ↑ | ↑ | ↑SNAIL | N/A | ↑migration and invasion | [128] |
| Colorectal cancer | Compound 11 | HCT116 cells in vitro | cells treated with compound 11 vs. untreated cells | ↑ | ↓ | ↓ | ↓ | N/A | N/A | ↓migration | [129] |
| Colorectal cancer | Compound 11 | HT29 cells in vitro | cells treated with compound 11 vs. untreated cells | N/A | N/A | N/A | N/A | N/A | N/A | ↓migration | [129] |
| Colorectal cancer | Compound 11 | HCT116 xenograft model in vivo | mice treated compound 11 vs. untreated mice | ↑ | N/A | ↓ | ↓ | N/A | N/A | ↓migration | [129] |
| Colorectal cancer | TSA | HT29, SW480, DLD1, HTC116 cells in vitro | cells treated with TSA vs. untreated cells | ↓ | N/A | N/A | ↑ | N/A | altered to spindle like morphology | →migration, ↑invasion only in DLD1 cells | [15] |
| Colorectal cancer | VPA | HT29, SW480, DLD1, HTC116 cells in vitro | cells treated with VPA vs. untreated cells | ↓ | N/A | N/A | ↑ | N/A | altered to spindle like morphology | →migration, ↑invasion in DLD1 and SW480 cells | [15] |
| Colorectal cancer | TGF-β1 | HT29, SW480, DLD1, HTC116 cells in vitro | cells treated with TGF-β1 vs. untreated cells | ↓ | N/A | N/A | ↑ | N/A | altered to spindle like morphology | ↑invasion only in DLD1 cells | [15] |
| Colorectal cancer | TSA+ TGF-β1 | HT29, SW480, DLD1, HTC116 cells in vitro | cells treated with TSA and TGF-β1 vs. untreated cells | ↓ | N/A | N/A | ↑ | N/A | altered to spindle like morphology | HT29 N/A, SW480 ↑migration, LDL1 →invasion, HTC116 N/A | [15] |
| Colorectal cancer | VPA + TGF-β1 | HT29, SW480, DLD1, HTC116 cells in vitro | cells treated with VPA and TGF-β1 vs. untreated cells | ↓ | N/A | N/A | ↑ | N/A | altered to spindle like morphology | HT29 N/A, SW480 ↑migration, LDL1 ↑migration, →invasion, HTC116 N/A | [15] |
| Renal cancer | VPA | Renca cells in vitro, mice in vivo | cells treated with VPA vs. untreated cells | ↓ | ↓ | N/A | ↓ | ↑TWIST1, ↓TWIST2 →SNAIL1, SNAIL2 |
interspace between cells after HDIs treatment | ↓migration | [130] |
| Renal cancer | MS-275 | Renca cells in vitro, mice in vivo | cells treated with MS-275 vs. untreated cells | ↓ | ↓ | N/A | N/A | N/A | interspace between cells after HDIs treatment | ↓migration | [130] |
| Renal cancer | TSA | HK2 cells in vitro | TGF-β1-pretreated HK2 cells treated with TSA vs. TGF-β1-treated HK2 cells | ↑ | N/A | → | N/A | N/A | N/A | N/A | [131] |
| Renal cancer | TSA | RPTEC cells in vitro | TGF-β1-pretreated RPTEC cells treated with TSA vs. untreated RPTEC cells | ↑ | N/A | N/A | N/A | →SMAD2, SMAD3 | from cuboidal to elongated form | N/A | [131] |
| Urothelial cancer | CDDP+SAHA | RT-112 and T-24 cells in cell culture or implanted on the chicken chorioallantoic membrane (CAM) | cells implanted on the CAM treated with CDDP + SAHA vs. cells treated with CDDP | N/A | N/A | N/A | N/A | N/A | CAM tumor reduction | [132] | |
| Urothelial cancer | CDDP+Romidepsin | RT-112 and T-24 cells in cell culture or implanted on the chicken chorioallantoic membrane (CAM) | cells implanted on the CAM treated CDDP+Romidepsin vs. cells treated with CDDP | N/A | N/A | N/A | N/A | N/A | CAM tumor reduction | [132] | |
| Prostate cancer | AR-42 | Ace-1 cells in vitro | cells treated with AR-42 vs. untreated cells | ↓ | → | ↓ | → | ↓TWIST, MYOF, ↑SNAIL, SLUG, PTEN, FAK, ZEB1 |
reduction of spindle like morphology | ↓migration and invasion | [133] |
| Prostate cancer | AR-42 | nude mice with implanted Ace-1 cells in vivo | mice with Ace-1 cells treated AR-42 vs. untreated mice | N/A | N/A | N/A | N/A | N/A | irregular shape of cell after AR42 treatment | ↓reduction of bone metastasis | [133] |
| Prostate cancer | SAHA, TSA, RGFP966 | LNCaP cells in vitro | cells treated with HDIs vs. untreated cells | N/A | N/A | N/A | ↑SAHA, TSA; →RGFP966 | ↓NKX1, FOXA1; ↑SLUG, ZEB1 (SAHA, TSA), →SLUG, ZEB1 (RGFP966) | N/A | ↑ migration (SAHA), N/A (TSA), →migration (RGFP99) | [134] |
| Prostate cancer | TSA | PC3 cells in vitro | cells treated with TSA vs. untreated cells | ↑ | N/A | N/A | ↓ | ↓SLUG | N/A | ↓migration and invasion | [13] |
| Prostate cancer | VPA | PC3 cells in vitro | cells treated with VPA vs. untreated cells | ↑ | N/A | N/A | N/A | N/A | N/A | ↓migration | [11] |
| Breast cancer | SAHA | MzChA-1 and TFK-1 cells in vitro | cells treated with SAHA pretreated with TGF-β1 vs. cells treated with TGF-β1 | ↑ | N/A | ↓ | ↓ | inhibition of p-SMAD2, p-SMAD3 and SMAD4 nuclear translocation induced by TGF-β1 | reduction of changes from valvate-like- to spindle-like shapes caused by TGF-β1 | N/A | [135] |
| Breast cancer | SAHA | MDA-MB-231 and BT-549 cells in vitro | cells treated with SAHA vs. untreated cells | ↓ | N/A | ↑ | ↑ | →SNAIL, SLUG, TWIST and ZEB expression and translocation | N/A | ↑migration | [136] |
| Breast cancer | SAHA, VPA | MDA-MB-231 and SUM159 cells in vitro | ed with VPA or SAHA vs. untreated cells | not detected | N/A | ↑ | ↑ | ↓FOXC3, ZEB1 ↑SNAIL2, TWIST1 | ↑sphere formation | ↑migration | [137] |
| Breast cancer | LBH589 | MDA-MB-231 and BT-549 cells in vitro | cell treated with LBH589 vs. untreated cells | ↑ | N/A | ↓ | ↓ | ↓ZEB1, ZEB2 | more epithelial phenotype | ↓migration and invasion | [138] |
| Breast cancer | LBH589 | MCF7 cells in vitro | cell treated with LBH589 vs. untreated cells | → | N/A | N/A | → | →ZEB1, ZEB2 | more epithelial phenotype | ↓migration and invasion | [138] |
| Breast cancer | MS-275 | MDA-MB-231 and Hs578T cells in vitro | cells treated with MS-275 vs. untreated cells | ↑ | N/A | ↓ | ↓ | ↓SNAIL, TWIST | more epithelial phenotype | ↓migration | [14] |
| Breast cancer | MS-275 | Balb c nude mice implanted with TRAIL resistant MDA-MB-468 cells in vivo | mice treated MS-275 vs. untreated mice | ↑ | N/A | N/A | ↓ | ↓ZEB1, SNAIL, SLUG | N/A | N/A | [139] |
| Breast cancer | MS-275+TRAIL | Balb c nude mice implanted with TRAIL resistant MDA-MB-468 cells in vivo | mice treated MS-275+TRAIL vs. mice treated TRAIL only | ↑ | N/A | N/A | ↓ | ↓ZEB1, SNAIL, SLUG | N/A | N/A | [139] |
| Ovarian cancer | TSA | SKOV3 cells in vitro | cells treated with TSA vs. untreated cells | ↓ | N/A | N/A | ↓ | N/A | N/A | ↓migration | [140] |
| Ovarian cancer | TSA+cisplatin | SKOV3 cells in vitro | cells treated with TSA + cisplatin vs. untreated cells | ↓ | N/A | N/A | ↓ | N/A | N/A | ↓migration | [140] |
| Ovarian cancer | TSA+cisplatin | Mice with HEY injected cells in vivo | mice treated with cisplatin followed by TSA vs. untreated mice | ↑ | N/A | N/A | ↓ | ↓SNAIL, SLUG, TWIST | N/A | N/A | [140] |
| Head and neck cancer | SAHA | Hep-2 and KB cells in vitro | cells treated with SAHA vs. untreated cells | ↑ | ↑ | N/A | ↓ | N/A | reduction of the spindle like morphology | ↓migration and invasion | [141] |
| Head and neck cancer | VPA | TE9 cells pretreated with TGF-β1 or irradiation in vitro | cells treated with VPA and TGF-β1 or irradiation before vs. cells treated with TGF-β1 or irradiation | ↑ | N/A | N/A | ↓ | ↓SMAD2 and SMAD3 phosphorylation, ↓TWIST, SNAIL, SLUG | reduction of spindle like morphology caused by TGF-β1 or irradiation | ↓migration and invasion | [142] |
| Malignant glioma | LBH589+irradiation | U251 cells in vitro | cells treated with LBH589+irradiation vs. untreated cells | ↑ | N/A | N/A | N/A | N/A | reduction of vasculogenic mimicry formation | ↓migration and invasion | [143] |
Abbreviations: ↑ increase, ↓ decrease, → no changes observed. SAHA-vorinostat, TSA-trichostatin A, VPA-valproic acid, MS-275 entinostat, NAB-sodium butyrate, LBH589-panobinostat, RAS2410-resminostat, 4SC-202-domatinostat, MGCD103-mocetinostat, compound 11-(E)-N-hydroxy-3-(1-(4-methoxyphenylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)acrylamide.