Prominent Role of Histone Modifications in the Regulation of Tumor Metastasis
Abstract
:1. Introduction
2. Epigenetic Modifications Regulate Epithelial to Mesenchymal Transition (EMT)
2.1. Activating Histone Modifications Involved in EMT
2.2. Repressive Histone Modifications Involved in EMT
2.3. DNA Methylation Involved in EMT
2.4. Non-Coding RNAs (Nc-RNAs) Involved in EMT
3. Epigenetic Modifications Involved in Intravasation and Anoikis Resistance
4. Epigenetic Modifications Involved in Extravasation and Colonization
5. Cancer-Type Specific Histone Modifications Regulating Tumor Metastasis
5.1. Head and Neck Cancer
5.2. Lung Cancer
5.3. Breast Cancer
5.4. Gastrointestinal Cancers
5.5. Prostate Cancer
6. Targeting Options
6.1. Low Molecular Weight EMT Inhibitors
6.2. Histone-Modifying Drugs
6.3. DNA Methylation Inhibitors
6.4. NcRNAs
Drug Category | Drug Name | Cancer Type | Effect | Reference | |
---|---|---|---|---|---|
LMW EMT inhibitors | BRD4 Inhibitors | MS417 | Colorectal | Inhibits metastasis via induction of E-cadherin and inhibition of Vimentin | [121] |
JQ1 | Breast | Blocks BRD4 binding to K73/K76Ac2 on the TWIST transcription factor, resulting in decreased WNT5A expression and inhibition of EMT and metastasis | [122] | ||
Histone binder inhibitor | UNC3866 | Prostate | Blocks the binding of CBX4/7 to methyl-lysine; unclarified role in EMT reversal | [124] | |
CSC targeting drugs | Salinomycin | Breast, GI, Leukemia, Lung, Prostate | Influences the Twist-Snail/ZEB-E-cadherin axis and Wnt-TGF-β-BMP to inhibit EMT | [126,127,128,129,130] | |
Histone-modifying drugs | DNMT Inhibitors | Chaetocin | AML | Restores E-cadherin and p15INK4B expression by reducing SUV39H1- mediated H3K9me3 on their promoters | [154] |
BIX01294 | HeLa cells | Induces E-cadherin expression by inhibiting G9a and GLP-mediated H3K9me2 deposition on its promoter. | [155,156] | ||
UNC0638 | Pancreatic | Induces E-cadherin expression by inhibiting G9a and GLP-mediated H3K9me2 deposition on its promoter. | [157] | ||
Zebularine | Pancreatic | Used in combination with SAHA to promote the differentiation of cancer cells | [137] | ||
HDAC Inhibitors | SAHA | Pancreatic | Combined with Zebularine in order to promote differentiation of cancer cells | [137] | |
Panobinostat | Hepatocellular | Inhibits cancer proliferation and induces apoptosis of cancer cells. Also increases differentiation markers in vivo | [135] | ||
Mocetinostat | Pancreatic | Specific antagonism of ZEB1-mediated silencing of miR-203, which is associated with tumor recurrence | [139] | ||
Entinostat | Breast | In phase III clinical trial | [143] | ||
PRMT5 Inhibitors | shRNA- mediated inhibition | Breast, Lung | Reduces metastatic potential, EMT and proliferation rate of cancer cells | [80,146] | |
EZH2 Inhibitors | Tazemetostat | Advanced solid tumors and lymphomas | Under clinical trial investigation | [152] | |
GSK2816126 | Lymphomas, solid tumors and MM | Clinical study terminated due to little effect in treatment efficiency | [152] | ||
Erk Inhibitors | AZD6244 | Breast | Combination with EZH2 inhibitors suppresses TGF-β-induced EMT | [150] | |
LSD1 Inhibitors | Parnate | Myelogenous leukemia | Decreases motility and invasiveness, increases E-cadherin | [158] | |
Pargyline | Lung | Suppresses proliferation, migration and invasion of cancer cells | [159,160] | ||
GSK2879552 | Lung | Clinical study discontinued | [161] | ||
DNA methylation inhibitors | Decitabine | MDS, AML | Changes cancer cell morphology, differentiation markers and inhibits proliferation | [163] | |
5-aza-2′-deoxycytidine | Gastric | Improves sensitivity to chemotherapy, restores epithelial phenotypes by promoting E-cadherin re-expression and inhibits EMT | [167,168] |
7. Conclusions—Future Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
EMT | Epithelial to Mesenchymal Transition |
P300/CBP | E1A Binding Protein P300/CREB Binding Protein |
ZEB1 | Zinc Finger E-Box Binding Homeobox 1 |
BRG1 | BRM/SWI2-Related Gene 1 |
CtBP | C-terminal-binding protein |
HDAC | Histone deacetylase |
SNAI1 | Snail Family of zinc finger proteins 1 |
SNAI2 | Slug |
JMJ3 | Jumonji Domain Containing 3 Histone Lysine Demethylase |
G9a | Euchromatic Histone Lysine Methyltransferase 2 |
SIN3A | SIN3 Transcription Regulator Family Member A |
SET8 | Lysine Methyltransferase 5A |
H | Histone |
K | Lysine |
me | methylation |
ac | acetylation |
R | Arginine |
TWIST1 | Twist Family BHLH Transcription Factor 1 |
EZH2 | Enhancer of Zeste 2 Polycomb Repressive Complex 2 Subunit |
PRC2 | Polycomb Repressive Complex 2 |
FZD7 | Frizzled Class Receptor 7 |
FLIP | CASP8 and FADD Like Apoptosis Regulator |
JMJD2B | Jumonji Domain-Containing Protein 2B |
PHF8 | PHD Finger Protein 8 |
NDRG1 | N-Myc Downstream Regulated 1 |
GLI1 | Glioma-Associated Oncogene Homolog 1 |
SMO | Smoothened, Frizzled Class Receptor |
FOXF1 | Forkhead Box F1 |
Bmi1 | Polycomb Complex Protein BMI-1 |
SIRT2 | Sirtuin 2 |
TGFBR2 | TGF-β Receptor type 2 |
GCN5 | General Control of Amino Acid Synthesis Protein 5-Like 2 |
PCAF | P300/CBP-Associated Factor |
TIP60 | Tat Interacting Protein, 60 kDa |
DDR | DNA Damage Response |
hMOF | Males-absent-on-the-first histone acetyltransferase |
TMS1 | Target of Methylation-induced Silencing |
ESR1 | Estrogen Receptor 1 |
Smad2 | Mothers Against Decapentaplegic Homolog 2 |
EPCAM | Epithelial Cell Adhesion Molecule |
ST14 | Suppression of Tumorigenicity 14 |
ESRP1 | Epithelial Splicing Regulatory Protein 1 |
RAB25 | RAB25, Member RAS Oncogene Family |
FLIP | CASP8 And FADD Like Apoptosis Regulator |
PRMT | Protein Arginine Methyltransferase |
MEP50 | Methylosome Protein 50 |
GAS1 | Growth Arrest Specific 1 |
PRC | Polycomb Repressive Complex |
KLF2 | Kruppel Like Factor 2 |
JARID | Jumonji, AT Rich Interactive Domain |
TRIM33 | Tripartite Motif Containing 33 |
Smad2/3 | Mothers Against Decapentaplegic Homolog 2/3 |
HP1 | Heterochromatin Protein 1-Alpha |
GSC | Goosecoid Homeobox |
MIXL1 | Mix Paired-Like Homeobox |
WDR5 | WD Repeat-Containing Protein 5 |
KDM6B | Lysine (K)-Specific Demethylase 6B |
ITG | Integrin |
UTX | Ubiquitously- Transcribed X Chromosome Tetratricopeptide Repeat Protein |
MMP-9/11 | Metalloproteinase-9/11 |
SIX1 | Sine Oculis Homeobox Homolog 1 |
MLL4 | Mixed-Lineage Leukemia Protein 4 |
ROCK kinase | Rho-Associated Protein Kinase 1 |
FOXC1 | Forkhead Box C1 |
SETDB1 | SET Domain Bifurcated Histone Lysine Methyltransferase 1 |
CDH1 | Cadherin 1 |
AXIN2 | Axis Inhibition Protein 2 |
NKD1 | Naked1 |
PPP2R2B | Protein Phosphatase 2 Regulatory Subunit 2 beta |
PRICKLE1 | Prickle Planar Cell Polarity Protein |
SFRP5 | Secreted Frizzled Related Protein 5 |
RKIP | Raf Kinase Inhibitory Protein |
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Markouli, M.; Strepkos, D.; Basdra, E.K.; Papavassiliou, A.G.; Piperi, C. Prominent Role of Histone Modifications in the Regulation of Tumor Metastasis. Int. J. Mol. Sci. 2021, 22, 2778. https://doi.org/10.3390/ijms22052778
Markouli M, Strepkos D, Basdra EK, Papavassiliou AG, Piperi C. Prominent Role of Histone Modifications in the Regulation of Tumor Metastasis. International Journal of Molecular Sciences. 2021; 22(5):2778. https://doi.org/10.3390/ijms22052778
Chicago/Turabian StyleMarkouli, Mariam, Dimitrios Strepkos, Efthimia K. Basdra, Athanasios G. Papavassiliou, and Christina Piperi. 2021. "Prominent Role of Histone Modifications in the Regulation of Tumor Metastasis" International Journal of Molecular Sciences 22, no. 5: 2778. https://doi.org/10.3390/ijms22052778