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Deregulated Chromatin Remodeling in the Pathobiology of Brain Tumors

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Abstract

Brain tumors encompass a heterogeneous group of malignant tumors with variable histopathology, aggressiveness, clinical outcome and prognosis. Current gene expression profiling studies indicate interplay of genetic and epigenetic alterations in their pathobiology. A central molecular event underlying epigenetics is the alteration of chromatin structure by post-translational modifications of DNA and histones as well as nucleosome repositioning. Dynamic remodeling of the fundamental nucleosomal structure of chromatin or covalent histone marks located in core histones regulate main cellular processes including DNA methylation, replication, DNA-damage repair as well as gene expression. Deregulation of these processes has been linked to tumor suppressor gene silencing, cancer initiation and progression. The reversible nature of deregulated chromatin structure by DNA methylation and histone deacetylation inhibitors, leading to re-expression of tumor suppressor genes, makes chromatin-remodeling pathways as promising therapeutic targets. In fact, a considerable number of these inhibitors are being tested today either alone or in combination with other agents or conventional treatments in the management of brain tumors with considerable success. In this review, we focus on the mechanisms underpinning deregulated chromatin remodeling in brain tumors, discuss their potential clinical implications and highlight the advances toward new therapeutic strategies.

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Abbreviations

4-PB:

4-Phenylbutyrate

ADP:

Adenosine-5′-diphosphate

AJAP1:

Adherens junctions associated protein 1, SHREW1

AKT:

RAC-alpha serine/threonine-protein kinase

AN-9:

Pivaloyloxymethyl butyrate

ANGPT1:

Angiopoietin-1

ARID1A:

AT-rich interactive domain-containing protein 1A

AT/RT:

Atypical teratoid/rhabdoid tumors

ATP:

Adenosine-5′-triphosphate

ATRX:

α-Thalassemia/mental retardation syndrome X-linked

Aza:

5-Aza-2′-deoxycitidine

Bak:

BCL2-antagonist/killer

Bax:

BCL2-associated X protein

BEX:

Brain-expressed X-linked

BIK:

BCL2-interacting killer

BLU:

Zinc finger MYND domain-containing protein 10

BMI-1:

BMI1 polycomb ring finger protein

BMP-2:

Bone morphogenetic protein 2

BRG1:

Brahma-related gene 1

BRM:

Drosophila trithorax group gene brahma

BTG2 (PC3):

B cell translocation gene 2

c-Myc:

V-myc myelocytomatosis viral oncogene homolog protein

c-Raf:

V-raf-1 murine leukemia viral oncogene homolog 1

CALCA:

Calcitonin

CASP8:

Caspase-8

CCND1:

Cyclin D1

CDH1:

Cadherin-1

CDKN1A:

Cyclin-dependent kinase inhibitor 1A

CDKN2A:

Cyclin-dependent kinase inhibitor 2A, isoform 4

CDKN2B:

Cyclin-dependent kinase 4 inhibitor B

CHD:

Chromodomain, helicase, DNA binding

CHI3L1 (YKL-40):

Chitinase-3-like protein 1

CITED4:

CBP/p300-interacting transactivator 4

COL1A2:

Collagen alpha-2(I) chain

COUP-TFII:

COUP transcription factor 2

CpG islands:

Cytosine-phosphate-guanine islands

CST6:

Cystatin E/M

CTCL:

Cutaneous T cell lymphoma

DAPK:

Death-associated protein kinase 1

DAXX:

Death-domain-associated protein

DHRS3:

Short-chain dehydrogenase/reductase 3

DKK1:

Dickkopf-1

DLC-1:

Deleted in liver cancer 1

DNMT:

DNA methyltransferase

DOT1L:

Histone-lysine N-methyltransferase, H3 lysine-79 specific

DR4:

Death receptor 4

DUSP3:

Dual specificity protein phosphatase 3

EHMT1:

Euchromatic histone-lysine N-methyltransferase 1

EMP3:

Epithelial membrane protein 3

EORTC/NCIC:

European Organization for Research and Treatment of Cancer/National Cancer Institute of Canada

EZH2:

Enhancer of zeste homolog 2 protein

FHIT:

Fragile histidine triad protein

FK228:

Romidepsin

G9A:

Euchromatic histone-lysine N-methyltransferase 2, EHMT2

GATA6:

GATA-binding protein 6

GBM:

Glioblastoma multiforme

GFAP:

Glial fibrillary acidic protein

GLI GLI:

Family zinc finger

GPR26:

G protein-coupled receptor 26

GSTP1:

Glutathione S-transferase P

GUCY1A3:

Guanylate cyclase 1A3

HAI-2/PB:

Hepatocyte growth factor activator inhibitor type-2/placental bikunin

HAT:

Histone acetyltransferase

HDAC:

Histone deacetylase

HDACI:

Histone deacetylase inhibitor

HGF:

Hepatocyte growth factor

HIC1:

Hypermethylated in cancer 1 protein

HKMT:

Histone-lysine methyltransferase

hMLH1:

HMLH1 protein

HOXA9:

Homeobox A9 protein

HP1:

Heterochromatin protein 1

HR23B RAD23:

Homolog B

HSP72:

Heat shock 70 kDa protein 1A

HSP90:

Heat shock protein 90 kDa alpha

ING1:

Inhibitor of growth 1

INO1:

Inositol-3-phosphate synthase 1

INO80:

Inositol requiring 80

ISWI:

Imitation SWI

JMJD1A:

Lysine-specific demethylase 3A, jumonji domain-containing 1A

JMJD1B:

Lysine-specific demethylase 3B, jumonji domain-containing 1B

JMJD2B:

Lysine-specific demethylase 4B, jumonji domain-containing 2B

JMJD2C:

Lysine-specific demethylase 4C, jumonji domain-containing 2C

KLF4:

Kruppel-like factor 4

KRT19:

Keratin, type I cytoskeletal 19

L3MBTL:

Lethal(3) malignant brain tumor-like protein

LBH589:

Panobinostat

LHX9:

Human Lim-homebox 9

lo-FGF-2:

Fibroblast growth factor-2

LSD1:

Lysine-specific demethylase 1

MAPK:

Mitogen-activated kinase-like protein

MCJ:

Methylation-controlled DNAJ

Mcl-1:

Myeloid cell leukemia 1

MGMT:

O-6-methylguanine-DNA methyltransferase

ΜLL:

Myeloid/lymphoid or mixed-lineage leukemia

MMP-2:

Matrix metallopeptidase 2

MRT:

Malignant rhabdoid tumor

MS275:

Entinostat

MT-3:

Metallothionein-3

MT1-MMP:

Membrane type-1 matrix metalloproteinase

MYOD1:

Myogenic differentiation 1

NAD:

Nicotinamide adenine dinucleotide

NDRG2:

N-myc downstream-regulated gene 2

NECL1:

Nectin-like molecule 1

NEURL1:

Neuralized 1

NF-κB:

Nuclear factor κappaB

Noxa:

NADPH oxidase activator 1

NQO1:

NAD(P)H dehydrogenase, quinone 1

NSCLC:

Non-small cell lung cancer

NSD1:

Nuclear receptor-binding SET domain protein 1

NuRD:

Nucleosome remodeling and deacetylation

p14/ARF:

Alternate reading frame product of the CDKN2A locus

p15INK4b:

Cyclin-dependent kinase 4 inhibitor B

p16INK4a:

Cyclin-dependent kinase inhibitor 2A, isoforms 1/2

p21WAF1/CIP1:

Cyclin-dependent kinase inhibitor 1A

PB:

Phenylbutyrate

PBMC:

Peripheral blood mononuclear cell

PCDHGA11:

Protocadherin gamma-A11

PDAM (TP73):

KIAA0495/p53-dependent apoptosis modulator

PDGFB:

Platelet-derived growth factor beta polypeptide

PEG3:

Paternally expressed gene 3

PHD:

Plant homeo-domain

PNET:

Primitive neuroectodermal tumor

PI3K:

Phosphatidylinositol 3-kinase

POU2F2:

POU domain, class 2, transcription factor 2

PRKCDBP:

Protein kinase C delta-binding protein

PROM1 (CD133):

Prominin 1

PSME2:

Proteasome (prosome, macropain) activator subunit 2

PTCH1–1C:

Patched homolog 1

PTEN:

Phosphatase and tensin homolog

PTGS2:

Prostaglandin-endoperoxide synthase 2

Rad51:

RAD51 homolog

RARB:

Retinoic acid receptor beta

RASL10A (RRP22):

RAS-like, family 10, member A

RASSF1A:

Ras association domain-containing protein 1A

RB1:

Retinoblastoma-associated protein

REN:

Renin

RTK:

Receptor tyrosine kinase

SAHA:

Suberoylanilide hydroxamic acid

SCNN1A:

Amiloride-sensitive sodium channel subunit alpha

SEC23A:

Sec23 homolog A

SET7:

Histone-lysine N-methyltransferase SET7

SET9:

Histone-lysine N-methyltransferase SET9

SETD7:

Histone-lysine N-methyltransferase SETD7

SETDB1:

Histone-lysine N-methyltransferase SETDB1

SFRP:

Secreted frizzled-related protein

Shh Sonic:

Hedgehog

Slit Slit homolog:

2 protein

SMARCA4:

SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4 or BRG1

SMARCB1 (INI1):

SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily b, member 1 or integrase interactor 1 protein

SMYD:

SET and MYND domain-containing protein

SN38:

Active metabolite of the topoisomerase I inhibitor irinotecan, CPT-11

SPINT2:

Serine peptidase inhibitor, Kunitz type, 2

Sox2:

SRY (sex determining region Y)-box 2

SUV39H:

Histone-lysine N-methyltransferase SUV39H

SWI/SNF:

SWItch/Sucrose NonFermentable

TCA:

Trichostatin A

TFPI-2:

Tissue factor pathway inhibitor

TGFBI:

Transforming growth factor-beta-induced protein ig-h3

THBS1:

Thrombospondin 1

THEM4 (CTMP):

Thioesterase superfamily member 4

TFRS-F10C:

Transferrin receptor-linked F10 gene

TIMP-2:

TIMP metallopeptidase inhibitor 2

TIMP3:

Metalloproteinase inhibitor 3

TMS1/ASC:

Target of methylation-induced silencing 1/Apoptosis-associated speck-like protein containing a CARD

TNF-α:

Tumor necrosis factor-alpha

TP14 (ARF):

Protamine TP14

TP73:

Tumor protein p73

TRAIL:

Tumor necrosis factor ligand superfamily member 10

TSP- 1:

Thrombospondin 1

TSPYL5:

Testis-specific protein, Y-encoded-like 5

UHRF1:

Ubiquitin-like with PHD and Ring finger domains 1

VHL:

Von Hippel-Lindau disease tumor suppressor

VPA:

Valproic acid

Wnt:

Wingless

ZIC2:

Zinc finger protein of cerebellum 2

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  1. Department of Biological Chemistry, Medical School, University of Athens, 75, M. Asias Street, 11527, Athens, Greece

    Anastasia Spyropoulou, Christina Piperi, Christos Adamopoulos & Athanasios G. Papavassiliou

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  1. Anastasia Spyropoulou
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  2. Christina Piperi
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  3. Christos Adamopoulos
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  4. Athanasios G. Papavassiliou
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Correspondence to Athanasios G. Papavassiliou.

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Anastasia Spyropoulou and Christina Piperi: equal contribution.

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Spyropoulou, A., Piperi, C., Adamopoulos, C. et al. Deregulated Chromatin Remodeling in the Pathobiology of Brain Tumors. Neuromol Med 15, 1–24 (2013). https://doi.org/10.1007/s12017-012-8205-y

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