Epigenetic Regulation of EMT (Epithelial to Mesenchymal Transition) and Tumor Aggressiveness: A View on Paradoxical Roles of KDM6B and EZH2
Abstract
:1. Introduction
1.1. Epithelial to Mesenchymal Transition (EMT)
1.2. Epigenetic Regulation of EMT
1.3. Current Described Roles of KDM6B and EZH2
2. EZH2 Is Associated to EMT and Cancer Aggressiveness
2.1. EZH2 Is Differently Expressed between Tumor and Normal Tissues in Various Cancer Types
2.2. EZH2 Modulates EMT by Targeting a Specific Subset of Genes
2.3. EZH2 Modulates EMT and Cancer Aggressiveness via Activating Gene Transcription, Independently of Its Methyltransferase Catalytic Activity
2.4. Regulation of EZH2 Expression during EMT
2.5. New Anti-Cancer Therapeutic Protocols Targeting EZH2 Activity
3. KDM6B in EMT and Cancer Aggressiveness
3.1. KDM6B Is Differently Expressed between Tumor and Normal Tissues in Various Cancer Types
3.2. KDM6B Modulates EMT by Targeting a Specific Subset of Genes
3.3. KDM6B Modulates Cancer Aggressiveness by Activating Gene Transcription, Independently of Its Demethylase Catalytic Activity
3.4. New Anti-Cancer Therapeutic Protocols Targeting KDM6B Activity
4. Conclusions
Funding
Conflicts of Interest
Abbreviations
ADP | Adenosine Diphosphate |
AKT | Protein Kinase B |
ALL | Akute Lymphoblastic Leukemia |
AMD1 | Adenosyl Methionine Decarboxylase 1 |
APC | Adenomatous Polyposis Coli |
ARF | Alternative Reading Frame |
BIM | BCL2 Like 11 |
BMP | Bone Morphogenetic Protein |
CDH1 | Cadherin 1 |
CDK | Cyclin Dependant Kinase |
CEBPA | CCAAT/Enhancer Binding Protein α |
ChIP | Chromatin ImmunoPrecipitation |
DLBCL | Diffuse Large B Cell Lymphoma |
DNA | Desoxyribonucleic Acid |
EED | Embryonic Ectoderm Development |
EGF | Epidermal Growth Factor |
EMT | Epithelial to Mesenchymal Transition |
EMT-ATF | Epithelial to Mesenchymal Transition Activating Transcription Factors |
EPCAM | Epithelial Cell Adhesion Molecule |
ER | Estrogen Receptor |
ERK | Extracellular Signal-Regulated Kinase |
EZH2 | Enhancer of Zeste Homolog 2 |
EZH2i | Enhancer of Zeste Homolog 2 Inhibitor |
FOS | FBJ Murine Osteosarcoma Viral Oncogene Homolog |
FOXO1 | Forkhead Box Protein O1 |
H2A | Histone 2A |
H2B | Histone 2B |
H3 | Histone 3 |
H3K27Ac | Histone 3, Lysine 27 Acetylated |
H3K27me2 | Histone 3, Lysine 27 Dimethylated |
H3K27me3 | Histone 3, Lysine 27 Trimethylated |
H3K27me3 | Histone 3, Lysine 27 Methylated |
HCC | Hepatocellular Carcinoma |
HDAC1 | Histone Deacetylase 1 |
HDAC2 | Histone Deacetylase 2 |
HER2 | Human Epidermal Growth Factor Receptor |
HOTAIR | HOX Transcript Antisense RNA |
HOX | Homeobox |
IF | ImmunoFluorescence |
IGF1 | Insulin-Like Growth Factor 1 |
IHC | Immunohistochemistry |
INK4 | Inhibitor of CDK4 |
JMJD3 | Jumonji Domain-Containing Protein 3 |
JUB1 | JUNGBRUNNEN 1 |
KDM6A | Lysine Demethylase 6A |
KDM6B | Lysine Demethylase 6B |
KMT6A | Lysine Methyltransferase 6A |
KO | Knock-Out |
KRAS | V-Ki-Ras2 Kirsten Rat Sarcoma Viral Oncogene Homolog |
lncRNA | Long Non-Coding RiboNucleic Acid |
MAPK | Mitogen-Activated Protein Kinase |
MEK | Mitogen-Activated Protein Kinase |
MET | Mesenchymal to Epithelial Transition |
miRNA | Micro Ribonucleic Acid |
MM | Multiple Myeloma |
MPM | Multiple Pleural Mesothelioma |
mRNA | Messenger RiboNucleic Acid |
N-CAD | N-Cadherin |
NF-κB | Nuclear Factor-κB |
NHL | Non-Hodgkin Lymphoma |
OCT4 | Octamer-Binding Transcription Factor 4 |
PDAC | Pancreatic Ductile Adenocarcinoma |
PD-L1 | Programmed Death Ligand 1 |
PRC2 | Polycomb Repressive Complex 2 |
PRE | Polycomb Repressive Complex 2 Response Element |
RBBP4 | RetinoBlastoma Binding Protein 4 |
RBBP7 | RetinoBlastoma Binding Protein 7 |
RelA | V-Rel Avian Reticuloendotheliosis Viral Oncogene Homolog A |
RelB | V-Rel Avian Reticuloendotheliosis Viral Oncogene Homolog B |
RKIP | Raf-1 Kinas Inhibitor Protein |
RNA | Ribonucleic Acid |
RT-PCR | Reverse Transcription Polymerase Chain Reaction |
RT-qPCR | Reverse Transcription Quantitative Polymerase Chain Reaction |
siRNA | Small Interfering RiboNucleic Acid |
SOX4 | SRY-Related HMG Box |
SUZ-12 | Suppressor of Zeste 12 |
TF | Transcription Factor |
tFL | Transformed Follicular Lymphoma |
TGF-β | Transforming Growth Factor β |
TIC | Tumor Initiating Cells |
TNF-α | Tumor Necrosis Factor α |
TRAIL | Tumor Necrosis Factor Related Apoptosis-Inducing Ligand |
UTR | Untranslated Region |
VIM | Vimentin |
ZEB | Zinc Finger E-box Binding Homeobox |
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Type of Histones Modification | Description | Effect on the Gene Expression |
---|---|---|
Acetylation | Acetylation of the lysine amino groups of histones | Decrease of histone/DNA interaction, chromatin is structurally loose, less compact, and transcription is activated |
Methylation | Methylation of arginine or lysine in histones | Arginine: transcription activation; lysine: activation or inhibition of transcription depending on the lysine targeted and the number of methyl groups added (mono-, di-, or tri-methylation) |
Ubiquitination | Mono-ubiquitylation of lysine of histones H2A and H2B | Regulation of transcription initiation and elongation |
Phosphorylation | Phosphorylation of serine, threonine or tyrosine of histones | DNA damage response (phosphorylation of H2AX), modulation of DNA compaction and interaction with other histone post translational modifications |
SUMOylation | SUMO protein conjugation on lysine of histones | Competition with other lysine modifications. Decrease and stop of transcription |
ADP ribosylation | Ribosyl-ADP addition on lysine of histones | DNA damage and transcription activation |
Arginine Citrullination | Transformation of an arginine into a citrulline residue | Decrease of DNA compaction |
Proline isomerization | Isomerization of a proline in cis conformation into a trans conformation | Modulation of histone methylation and transcription |
Cancer Type | Over/Under Expressed | Technique | Ref. |
---|---|---|---|
Clear cell renal cell carcinomas (ccRCC) | Overexpressed in metastasis | IHC | [29] |
Clear cell renal cell carcinomas (ccRCC) | Overexpressed in aggressive and invasive carcinomas | IHC | [28] |
Esophagus squamous cell carcinomas | Overexpressed | IHC | [30] |
Bladder urothelial carcinomas | Overexpressed in invasive and aggressive carcinomas | RT-qPCR on cell lines and tissues | [39] |
Urothelial carcinomas | Overexpressed | Tissue microassays/IHC | [38] |
Cutaneous melanomas and cancers of the endometrium, prostate and breast | Overexpressed | IHC, Tissue microarray | [31] |
Human and murine melanomas | Overexpressed | IF | [40] |
Hormone refractory, metastatic prostate cancers | Overexpressed | Gene expression profiling | [37] |
Gastric cancers | Overexpressed and correlated with aggressiveness and invasion | IHC | [35] |
Breast carcinomas | Overexpressed in invasive tumors | Tissue microarray | [34] |
Ovarian carcinomas | Overexpressed | IHC | [36] |
Lung Adenocarcinoma | Overexpressed in poor prognosis tumors | IHC | [32] |
Adult and pediatric brain tumors | Overexpressed | IHC | [33] |
Lung adenocarcinomas | Inactivating mutations in 14% of the cohort samples | Sequencing | [38] |
Myelodysplastic syndromes/Myeloproliferative neoplasms | Inactivating mutations | Extensive mutation analyses | [42] |
Tissue of Origin of the Cell Line | Name of the Cell Line | Genes Regulated | Direct/Indirect | Ref. |
---|---|---|---|---|
Head and neck squamous cell carcinoma | FaDu and SNU1041 | Down-regulation of N-CADHERIN and VIMENTIN | Unknown | [43] |
Up regulation of E-CADHERIN | ||||
Ovarian cancer | SKOV3 and Kuramochi | Down-regulation of ZEB2, VIMENTIN, N-CADHERIN | Direct | [44] |
Colon cancer | HT-29 M6 | Down-regulation of CDH1 | Direct | [50] |
Non-small cell lung cancer | A549 | Down-regulation of CDH1 | Direct | [51] |
Ovarian cancer | HO-8910 | Down-regulation of CDH1, Up-regulation of TGF-β1 | Unknown | [36] |
Prostate cancer | PC3 | Down-regulation of ADRB2, DAB2IP, CDH1 and CDKN2A | Unknown | [53] |
Prostate and breast cancer | LnCAP, MCF7, DU-145 and LSHAR | Down-regulation of RKIP | Direct | [57] |
Human and murine melanomas | XB2, Melan-a, HEK293T, B16F1 and B16F10 | Down-regulation of AMD1, DCK and WDR19 | Direct | [40] |
Small cell lung cancer | DMS53, Lul30, H209 | Down-regulation of JUB | Direct | [58] |
Pancreatic cancer | MIA-PaCa2 and Panc04.03 | Down-regulation of p27kip | Direct | [59] |
Liver hepatocellular carcinoma | huh-7 and Hep-3B | Down-regulation of APC | Direct | [60] |
Non-small cell lung carcinoma | H358 and A549 | Down-regulation of IGF1 | Unknown | [41] |
Down-regulation of AKT and ERK (via IGF1) | Indirect | |||
ER-negative breast cancer | MDA-MB-231 | Down-regulation of NF-κB target genes | Unknown | [61] |
ER-positive luminal like breast cancer | MCF7 | Up-regulation of NF-κB target genes by binding of RelA and RelB | Direct | [61] |
Breast cancer | MCF-7 | Up-regulation of C-MYC and CYCLIN D1 | Direct | [62] |
Title | Phase | Inhibitor | Cancer |
---|---|---|---|
A phase 1 study of SHR2554 in subjects with relapsed or refractory mature lymphoid neoplasms | Phase 1 | SHR2554 | Relapsed or refractory mature lymphoid neoplasms |
A phase 1 study of the EZH2 inhibitor tazemetostat in pediatric subjects with relapsed or refractory INI1-negative tumors or synovial sarcoma | Phase 1 | Tazemetostat | Rhabdoid tumors, INI1-negative tumors, Synovial sarcoma and malignant rhabdoid tumor of ovary |
A phase II, multicenter study of the EZH2 inhibitor tazemetostat in adult subjects with INI-1-negative tumors or relapsed/refractory synovial sarcoma | Phase 2 | Tazemetostat | Malignant rhabdoid tumors, rhabdoid tumors of the kidney, atypical teratoid rhabdoid tumors and eight more. |
ProSTAR: A study evaluating CPI-1205 in patients with metastatic castration resistant prostate cancer | Phase 1/2 | CPI-1205 | Metastatic castration resistant prostate cancer (mCRPC) |
ORIOn-E: A study evaluating CPI-1205 in patients with advanced solid tumors | Phase 1/2 | CPI-1205 | Advanced solid tumors |
Study of the EZH2 Inhibitor Tazemetostat in malignant mesothelioma | Phase 2 | Tazemetostat | Mesothelioma, BAP1 loss of function |
Open-label, multicenter, phase 1/2 study of tazemetostat (EZH2 histone methyl transferase (HMT) inhibitor as a single agent in subjects with advanced solid tumors or with B-cell lymphomas and Tazemetostat in combination with Prednisolone in subjects with DLBCL | Phase 1/2 | Tazemetostat | B-cell lymphomas, advanced solid tumors, diffuse large B-cell lymphoma (and 3 more) |
A study evaluating CPI-1205 in patients with B-cell lymphomas | Phase 1 | CPI-1205 | B-cell lymphoma |
Tazemetostat in treating patients with relapsed or refractory advanced solid tumors, non-Hodgkin lymphoma, or histiocytic disorders with EZH2, SMARCB1, or SMARCA4 gene mutations (a pediatric match treatment trial) | Phase 2 | Tazemetostat | Advanced malignant solid neoplasm, Ann Arbor stage II childhood Hodgkin lymphoma (and 47more) |
A study to investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of GSK2816126 in subjects with relapsed/refractory diffuse large B-cell lymphoma, transformed follicular lymphoma, other non-Hodgkin’s lymphomas, solid tumors, and multiple myeloma | Phase 1 | GSK2816126 | Cancer |
Safety and efficacy of MAK683 in adult patients with advanced malignancies | Phase 1/2 | MAK683 | Diffuse large B-cell lymphoma |
Cancer Type | Over/Under Expressed | Technique | Ref. |
---|---|---|---|
Hepatocellular carcinoma | Overexpressed | Tissue RT-qPCR and Western blotting | [76] |
Clear cell renal cell Carcinoma | Overexpressed | Tissue RT-qPCR, Western blotting, and IHC | [77] |
Multiple Myeloma | Overexpressed | Public data set study | [78] |
Hodgkin‘s lymphoma | Overexpressed | IHC | [79] |
Breast cancer | Overexpressed | Oncomine data analysis | [80] |
Malignant pleural mesothelioma | Overexpressed | Tissue RT-qPCR | [81] |
Ovarian cancer | Overexpressed | IHC and tissue RT-qPCR | [82] |
Pancreatic ductal adenocarcinoma | Under-expressed in invasive tumors compared to low grade cancers | Tissue microarray | [83] |
Colon cancer | Under-expressed in poor differentiated tumors | Tissue RT-qPCR | [84] |
Colorectal cancer | Under-expressed | IHC | [85] |
Tissue of Origin | Cell Line | Genes Regulated | Direct/Indirect | Ref. |
---|---|---|---|---|
Mouse breast | NmuMG | Up-regulation of SNAI1 | Direct | [80] |
Hepatocarcinoma | HepG2 | Up-regulation of SNAI2 | Direct | [76] |
Clear cell renal cell carcinoma | Caki-2 | Up-regulation of SNAI2 | Direct | [77] |
Renal cell carcinoma | ACHN | Up-regulation of SNAI1 | Unknown | [86] |
Colon carcinoma | SW-480 | Down-regulation of SNAI1, ZEB1, and ZEB2 | Unknown | [84] |
Colorectal carcinoma | HCT116 | Up-regulation of EpCAM | Direct | [87] |
Ovarian cancer | SKOV-3 | Up-regulation of HER2 | Direct | [89] |
Breast cancer | MCF-7 and MDA-MB-231 | Up-regulation of NANOG, SOX2, OCT3 | Unknown | [90] |
Pancreas adenocarcinoma | BxPC3 | Up-regulation of CEBPA | Direct | [83] |
Skin, foreskin | BJ | Up-regulation of p53 target genes | Direct (via p53 binding) | [22] |
Melanoma | A375-LM3 | Up-regulation of BMP2; BMP4, CCL2, STC1 TFPI2, PTGS2 and TGM2 | Direct | [91] |
Multiple myeloma | MM-1S | Up-regulation of ELK1 and FOS | Direct | [78] |
Lung | IMR-90 | Up-regulation of INK4a | Direct | [92] |
Lung fibroblast | TIG-3 | Up-regulation of INK4A | Direct | [94] |
Immortalized Human embryonic kidney cells | HEK-293 | Stabilization of nuclear p53 | Direct | [95] |
Non-small cell lung cancer | H460 and A549 | Stabilization of FOXO1 in nucleus | Direct | [96] |
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Lachat, C.; Boyer-Guittaut, M.; Peixoto, P.; Hervouet, E. Epigenetic Regulation of EMT (Epithelial to Mesenchymal Transition) and Tumor Aggressiveness: A View on Paradoxical Roles of KDM6B and EZH2. Epigenomes 2019, 3, 1. https://doi.org/10.3390/epigenomes3010001
Lachat C, Boyer-Guittaut M, Peixoto P, Hervouet E. Epigenetic Regulation of EMT (Epithelial to Mesenchymal Transition) and Tumor Aggressiveness: A View on Paradoxical Roles of KDM6B and EZH2. Epigenomes. 2019; 3(1):1. https://doi.org/10.3390/epigenomes3010001
Chicago/Turabian StyleLachat, Camille, Michaël Boyer-Guittaut, Paul Peixoto, and Eric Hervouet. 2019. "Epigenetic Regulation of EMT (Epithelial to Mesenchymal Transition) and Tumor Aggressiveness: A View on Paradoxical Roles of KDM6B and EZH2" Epigenomes 3, no. 1: 1. https://doi.org/10.3390/epigenomes3010001