Epigenetics and cancer

In the paper

“In contrast to genetic cancer causes, the possibility of reversing epigenetic codes may provide new targets for therapeutic intervention.”

In the paper

“Aside from the core histones, a variety of variant histone proteins exist and can be inserted into the nucleosome, possibly serving as landmarks for specific cellular functions (discussed following).”

In the paper

“Surprisingly, although PRC2 complex members are directly controlled by the RB tumor-suppressor pathway, their expression levels do not appear to fluctuate in a cell cycle-dependent manner (Weinmann et al. 2001;Bracken et al. 2003).”

What the sources say

• Not checked yetcites Weinmann et al. 2001
• Not checked yetcites Bracken et al. 2003

In the paper

“This is exemplified in gene activation where phosphorylation of histone H3 Ser 10 facilitates acetylation of Lys 14 and methylation of Lys 4, resulting in an open chromatin conformation (Cheung et al. 2000;Lo et al. 2000).”

What the sources say

• Not checked yetcites Cheung et al. 2000
• Not checked yetcites Lo et al. 2000

In the paper

“The pattern of histone modifications signifies the status of the chromatin locally and has been coined the histone code (Strahl and Allis 2000).”

What the sources say

• Not checked yetcites Strahl and Allis 2000

In the paper

“Epigenetic programming is crucial in mammalian development, and stable inheritance of epigenetic settings is essential for the maintenance of tissue-and cell-typespecific functions (Li 2002).”

What the sources say

• Not checked yetcites Li 2002

In the paper

“These functions point to long-range mechanisms of transcriptional repression and suggest that PRC2 activity may have global consequences to the cell, perhaps via more generally skewing the balance between specific histone methylation imprints.”

In the paper

“histone methylations can serve as anchorage points for both activator and repressor complexes and are thereby involved in conferring an epigenetic inheritance to the cell, carrying information related to differentiation commitment and function.”

In the paper

“The nucleosome is made up of approximately two turns of DNA wrapped around a histone octamer built from two subunits of each histone, H2A, H2B, H3, and H4, respectively, In between core nucleosomes, the linker histone H1 attaches and facilitates further compaction (for a recent review, see Khorasanizadeh 2004).”

What the sources say

• Not checked yetcites Khorasanizadeh 2004

In the paper

“Polycomb-group (PcG) proteins form transcriptional repressor modules that functionally can be divided into at least two distinct complexes: the initiation complex, Polycomb repression complex 2 (PRC2), the core of which in humans consists of EZH2, EED, and SUZ12; and the maintenance complex, PRC1, with the core proteins RNF2, HPC, EDR, and BMI1.”

In the paper

“Al-though histone acetylation in general correlates with transcriptional activity,”

In the paper

“however, experimental overexpression of EZH2 results in target gene suppression only (Varambally et al. 2002), and hence does not sustain a notion of dominant negative effects.”

What the sources say

• Not checked yetcites Varambally et al. 2002

In the paper

“and the observed overexpression of EZH2 in cancers is likely causally related to tumorigenesis and not a mere consequence of deregulated RB-E2F functioning, as the EZH2 locus is amplified in several cancers (Bracken et al. 2003).”

What the sources say

• Not checked yetcites Bracken et al. 2003

In the paper

“Although most histone modifications are reversible, no histone demethylase has been identified as yet, suggesting histone methylation to be involved in processes of long-term regulation.”

In the paper

“The N-terminal tails of the histone proteins are protruding out from the nucleosomal core particles, and these tails serve as regulatory registers onto which epigenetic signals can be written.”

In the paper

“Recent data have demonstrated that the SET domain present in EZH2 is responsible for methylation of Lys 9 and, more prominently, Lys 27 of histone H3 (Cao et al. 2002;Czermin et al. 2002;Kuzmichev et al. 2002;Muller et al. 2002) and Lys 26 on histone H1 (Kuzmichev et al. 2004).”

What the sources say

• Not checked yetcites Cao et al. 2002
• Not checked yetcites Czermin et al. 2002
• Not checked yetcites Kuzmichev et al. 2004

In the paper

“Also DNA methylation affects histone modifications and vice versa, to make up a highly intricate epigenetic control mechanism, the impact of which we have only just begun to comprehend.”

In the paper

“Members of both PcG and TrxG protein complexes harbor SET domains.”

In the paper

“The PRC2 complex is also required for X-chromosome inactivation (Plath et al. 2003;Silva et al. 2003) and for correct imprinting of autosomal loci (Wang et al. 2001b).”

What the sources say

• Not checked yetcites Plath et al. 2003
• Not checked yetcites Silva et al. 2003
• Not checked yetcites Wang et al. 2001b

In the paper

“Covalent modification of histones includes acetylation of lysines, methylation of lysines and arginines, phosphorylations of serines and threonines, ADP-ribosylation of glutamic acids, and ubiquitination and sumolyation of lysine residues (Fig. 1).”

In the paper

“Histone proteins can be mono-, di-, or trimethylated at the ␧ amino group of lysine residues and either mono-or dimethylated at arginine residues.”

In the paper

“This, however, remains to be confirmed in mouse models.”

In the paper

“SMYD3 was found to interact with the RNA polymerase II complex and activate target genes via methylation of histone H3 Lys 4.”

In the paper

“Evi1 was characterized in the mouse as a cancer-related retroviral integration site in myeloid leukemia (Morishita et al. 1988), and EVI1 was subsequently identified as a translocation breakpoint in hu-mans (Morishita et al. 1992).”

What the sources say

• Not checked yetcites Morishita et al. 1988
• Not checked yetcites Morishita et al. 1992

In the paper

“Mll heterozygous mice do not appear tumor prone, making haploinsufficiency a less likely cause of leukemogenesis (Corral et al. 1996).”

What the sources say

• Not checked yetcites Corral et al. 1996

In the paper

“Whereas Suv39h deficiency in the mouse predominantly was found to affect heterochromatin stability, the Suv39h methyltransferases associate with numerous proteins involved in cell cycle regulation including pRB (Nielsen et al. 2001;Vandel et al. 2001), PcG-proteins (Sewalt et al. 2002), and SMADs (Frontelo et al. 2004).”

What the sources say

• Not checked yetcites Nielsen et al. 2001
• Not checked yetcites Vandel et al. 2001
• Not checked yetcites Sewalt et al. 2002

In the paper

“SUV39H1 is the mammalian homolog of the Drosophila position effect variegation modifier Su(var)3-9 and was the first SET domain protein to be recognized as a histone methyl transferase (Rea et al. 2000).”

What the sources say

• Not checked yetcites Rea et al. 2000

In the paper

“The Ash1-specific methylation imprint was found to displace HP1 and PcG proteins, which are normally bound to repressed genes, and instead facilitates the binding of the Brahma chromatin remodeling complex (Beisel et al. 2002).”

What the sources say

• Not checked yetcites Beisel et al. 2002

In the paper

“This suggests a functional redundancy between different epigenetic gene repression mechanisms, which may serve to explain why loss of Suv39h-mediated repression does not have an even stronger phenotype.”

In the paper

“Intriguingly, all fusion proteins retain the N-terminal part of MLL1, whereas the C-terminal part encoding the SET domain is lost.”

In the paper

“In accordance with a tumor-suppressive function of RIZ1, ectopic expression in cancer cell lines results in cell cycle arrest and/or apoptosis (He et al. 1998;Jiang et al. 1999).”

What the sources say

• Not checked yetcites He et al. 1998
• Not checked yetcites Jiang et al. 1999

In the paper

“RIZ1, originally isolated from its interaction with the RB tumor suppressor protein (Buyse et al. 1995), was the first SET domain protein demonstrated to be a tumor suppressor (Steele-Perkins et al. 2001).”

What the sources say

• Not checked yetcites Buyse et al. 1995
• Not checked yetcites Steele-Perkins et al. 2001

In the paper

“Mice deficient for the two Suv39 homologs display chromosomal instability and are prone to develop B-cell lymphomas resembling human non-Hodgkin lymphomas, albeit with long latency (Peters et al. 2001).”

What the sources say

• Not checked yetcites Peters et al. 2001

In the paper

“In embryonic stem (ES) cells lacking both Suv39 homologs the pericentromeric heterochromatin is devoid of the characteristic trimethylation of histone H3, Lys 9. Instead, an alternative methylation imprint consisting of monomethylated Lys 9 and trimethylated Lys 27 has accumulated (Peters et al. 2003).”

What the sources say

• Not checked yetcites Peters et al. 2003

In the paper

“The 5Ј MDS part of MDS-EVI1 contains a SET domain, and both retroviral integrations in the mouse and translocations in humans result in the selective overexpression of the EVI1 variant lacking a SET domain.”

In the paper

“SMYD3 was recently identified as a SET and MYND domain-containing protein overexpressed in colorectal carcinomas and hepatocellular carcinomas (Hamamoto et al. 2004).”

What the sources say

• Not checked yetcites Hamamoto et al. 2004

In the paper

“Interestingly, only RIZ1 harbors a SET domain and appears to be the main target of inactivation in tumors (Huang 2002),”

What the sources say

• Not checked yetcites Huang 2002

In the paper

“Whereas the oncogenic capacity of SMYD3 is yet to be confirmed in an in vivo model, overexpression of SMYD3 results in colony formation of NIH 3T3 cells.”

In the paper

“The reduced histone H3 methylation resulting from loss of Suv39h caused a decrease in HP1 association to the telomeres and abnormal telomere elongation (Garcia- Cao et al. 2004).”

What the sources say

• Not checked yetcites Garcia-Cao et al. 2004

In the paper

“More than 40 specific translocations involving MLL1 have been described in human cancers to date (Ayton and Cleary 2001).”

What the sources say

• Not checked yetcites Ayton and Cleary 2001

In the paper

“Interestingly, the MYND domain appears to confer sequence-specific binding to target genes.”

In the paper

“Likewise, RNAi-mediated knockdown of HDAC2 in colonic cancer cells resulted in cell death, indicating a role for HDAC2 in protecting cancer cells against apoptosis (Zhu et al. 2004a).”

What the sources say

• Not checked yetcites Zhu et al. 2004a

In the paper

“Aside from histones, many transcriptional regulators, chromatin modifiers, and intracellular signal transducers are posttranslationally modified by acetylation.”

In the paper

“Dnmt1 was shown to be necessary and sufficient for Fos-induced transformation of mouse fibroblast cells (Bakin and Curran 1999),”

What the sources say

• Not checked yetcites Bakin and Curran 1999

In the paper

“On the other hand is the reliance of important tumorsuppressor mechanisms on HDAC function, as exemplified by the dependency of RB on HDAC1 for transcriptional repression of E2F target genes (Luo et al. 1998;Magnaghi-Jaulin et al. 1998;Robertson et al. 2000).”

What the sources say

• Not checked yetcites Luo et al. 1998
• Not checked yetcites Magnaghi-Jaulin et al. 1998
• Not checked yetcites Robertson et al. 2000

In the paper

“DNA methylation is tightly connected to cancer development and can act as a double-edged sword.”

In the paper

“DNMT1 associates with the DNA replication fork and functions as a hemi-methylase responsible for maintaining correct methylation patterns on DNA replication.”

In the paper

“All three methyltransferase enzymes have been found to be overexpressed in human tumors, although to moderate levels only (De Marzo et al. 1999;Robertson et al. 1999;Girault et al. 2003;Nagai et al. 2003).”

What the sources say

• Not checked yetcites De Marzo et al. 1999
• Not checked yetcites Robertson et al. 1999
• Not checked yetcites Girault et al. 2003

In the paper

“CpG islands are most often associated with promoter regions and an estimated 60% of human genes contain a CpG island (Antequera and Bird 1993).”

What the sources say

• Not checked yetcites Antequera and Bird 1993

In the paper

“Germ-line mutations in DNMT3B underlies ICF syndrome, a rare disorder characterized by immunodeficiency, centromeric instability, and facial abnormalities (Hansen et al. 1999;Xu et al. 1999).”

What the sources say

• Not checked yetcites Hansen et al. 1999
• Not checked yetcites Xu et al. 1999

In the paper

“Hdac1-deficient mice are not viable and ES cells with homozygous Hdac1 deletion display proliferation defects correlating with increased levels of the cyclin-dependent kinase inhibitors p21 and p27 (Lagger et al. 2002), demonstrating the involvement of HDAC1 in cell cycle regulation.”

What the sources say

• Not checked yetcites Lagger et al. 2002

In the paper

“Germ-line mutations in CBP causes the developmental disorder Rubenstein-Taybi syndrome, and these patients suffer an increased cancer risk (Petrij et al. 1995;Murata et al. 2001).”

What the sources say

• Not checked yetcites Petrij et al. 1995
• Not checked yetcites Murata et al. 2001

In the paper

“Although no arginine-specific methyltransferases have been implicated in cancer development yet, several of these enzymes are involved in gene regulatory complexes important for cell cycle regulation.”

In the paper

“PRMT5 was furthermore found to associate with and negatively regulate the cyclin E promoter (Fabbrizio et al. 2002).”

What the sources say

• Not checked yetcites Fabbrizio et al. 2002

In the paper

“Patterns of DNA methylation are laid out during early embryogenesis via the interplay of at least three active DNA methyltransferases, DNMT1, DNMT3A, and DNMT3B, and targeted deletions of these genes in the mouse have demonstrated that the enzymes are essential for normal development (Li et al. 1992;Okano et al. 1999).”

What the sources say

• Not checked yetcites Li et al. 1992
• Not checked yetcites Okano et al. 1999

In the paper

“Methylation at the C-5 position of cytosine residues present in CpG dinucleotides by DNMTs has evolved relatively late in evolution and is generally considered to facilitate static long-term gene silencing and to confer genome stability through repression of transposons and repetitive DNA elements (Yoder et al. 1997).”

What the sources say

• Not checked yetcites Yoder et al. 1997

In the paper

“Recently, Hdac2 was genetically linked to the Wnt pathway, as Hdac2 is overexpressed in tumors and tissues from mice lacking the adenomatosis polyposis coli (APC) tumor suppressor (Zhu et al. 2004a).”

What the sources say

• Not checked yetcites Zhu et al. 2004a

In the paper

“The PRMT5 arginine methyltransferase can methylate both histone H3 and H4 in vitro and interacts directly with components of the SWI/SNF complex (Pal et al. 2003).”

What the sources say

• Not checked yetcites Pal et al. 2003

In the paper

“Interestingly, mouse embryo fibroblasts deficient for Dnmt3b are resistant to transformation by SV40 largeT and activated Ras oncogenes (Soejima et al. 2003), demonstrating that epigenetic and genetic mechanisms likely act in concert during cellular transformation.”

What the sources say

• Not checked yetcites Soejima et al. 2003

In the paper

“On the one hand, oncogenesis is promoted by local hypermethylation of tumor-suppressor genes, whereas global genomic hypomethylation, on the other hand, affects oncogene expression and genomic stability (Jones and Baylin 2002).”

What the sources say

• Not checked yetcites Jones and Baylin 2002

In the paper

“Acetylation of histone proteins correlates with transcriptional activation and a dynamic equilibrium of histone acetylation is governed by the opposing actions of HATs and histone deacetylases (HDACs) (for recent reviews, see Marks et al. 2001;Yang 2004).”

What the sources say

• Not checked yetcites Marks et al. 2001
• Not checked yetcites Yang 2004

In the paper

“CpG dinucleotides are statistically underrepresented in the genome, likely because methylation of cytosine makes them more susceptible to deamination, but are locally enriched in shorter stretches of DNA (0.5 to several kilobases) known as CpG islands (Bird 2002).”

What the sources say

• Not checked yetcites Bird 2002

In the paper

“Both genes reside in regions frequently lost in tumors, and cancerspecific mutations abolishing the enzymatic activity of p300 have been identified (Muraoka et al. 1996;Gayther et al. 2000;Ozdag et al. 2002).”

What the sources say

• Not checked yetcites Muraoka et al. 1996
• Not checked yetcites Gayther et al. 2000
• Not checked yetcites Ozdag et al. 2002

In the paper

“the regulatory regions of many genes (including known tumor suppressors) contain islands of repetitive sequences, some of which have been shown to influence transcriptional regulation (Jordan et al. 2003;Kelly 2003).”

What the sources say

• Not checked yetcites Jordan et al. 2003
• Not checked yetcites Kelly 2003

In the paper

“Loss of imprinting of the IGF2 gene was recently suggested as a predictive marker for colorectal cancer (Cui et al. 2003).”

What the sources say

• Not checked yetcites Cui et al. 2003

In the paper

“CTCF is involved in the regulation of imprinting, where it is required to protect against de novo methylation (Fedoriw et al. 2004;Lewis and Murrell 2004).”

What the sources say

• Not checked yetcites Fedoriw et al. 2004
• Not checked yetcites Lewis and Murrell 2004

In the paper

“Also, hypermethylation of tumor-suppressor genes may be an early event in cancer development (Waki et al. 2003;Lee et al. 2004;Suter et al. 2004), suggesting that epigenetic and mutational cancer causes may collaborate from an early time point in disease progression.”

What the sources say

• Not checked yetcites Waki et al. 2003
• Not checked yetcites Lee et al. 2004
• Not checked yetcites Suter et al. 2004

In the paper

“it has been suggested that DNMTs may preferentially bind to damaged or mismatched DNA (James et al. 2003).”

What the sources say

• Not checked yetcites James et al. 2003

In the paper

“Epigenetic induction of a classical mutator phenotype via transcriptional inactivation of the DNA mismatch repair gene MLH1 has been proposed to account for microsatellite instability in colorectal cancers (Kane et al. 1997;Herman et al. 1998;Toyota et al. 1999a,b),”

What the sources say

• Not checked yetcites Kane et al. 1997
• Not checked yetcites Herman et al. 1998
• Not checked yetcites Toyota et al. 1999a,b

In the paper

“In contrast to hypermethylation of tumor-suppressor genes, tumor cells globally display an overall hypomethylation of DNA (Feinberg and Vogelstein 1983a;Goelz et al. 1985) and hypomethylation was the first epigenetic mechanism to be linked to cancer development (Feinberg and Tycko 2004).”

What the sources say

• Not checked yetcites Feinberg and Vogelstein 1983a
• Not checked yetcites Goelz et al. 1985
• Not checked yetcites Feinberg and Tycko 2004

In the paper

“Global genomic demethylation appears to progress with age in a tissue-dependent manner (Richardson 2003) and may in part explain the higher incidence of cancer among the elderly.”

What the sources say

• Not checked yetcites Richardson 2003

In the paper

“Genomic hypomethylation may furthermore cause genomic instability, presumably because demethylation predisposes to DNA strand breakage and recombination within derepressed repetitive sequences (for review, see Ehrlich 2002).”

What the sources say

• Not checked yetcites Ehrlich 2002

In the paper

“BRG1/BRM expression was found lost in 10% of primary lung tumors correlating with a poor prognostic outcome (Reisman et al. 2003).”

What the sources say

• Not checked yetcites Reisman et al. 2003

In the paper

“Noncoding antisense RNA driving DNA methylation”

In the paper

“The H2A variant H2AX marks DNA double-strand breaks, and H2AX-deficient cells have increased genomic instability and impaired forma-tion of radiation-induced foci of DNA repair proteins such as BRCA1 (Bassing et al. 2002;Celeste et al. 2002).”

What the sources say

• Not checked yetcites Bassing et al. 2002
• Not checked yetcites Celeste et al. 2002

In the paper

“DNA methylation driving histone modification”

In the paper

“In both mammals and flies, HP1 acts in a dosage-dependent manner with heterozygotes displaying a partial loss of gene silencing and HP1 overexpression resulting in an increase in silencing (Eissenberg et al. 1992;Festenstein et al. 1999).”

What the sources say

• Not checked yetcites Eissenberg et al. 1992
• Not checked yetcites Festenstein et al. 1999

In the paper

“Histone modification directing DNA methylation”

In the paper

“HP1␣ and HP1␤ localize to pericentric heterochromatin and minor sites within euchromatin, whereas HP1␥ localizes predominantly to euchromatic regions (Eissenberg and Elgin 2000).”

What the sources say

• Not checked yetcites Eissenberg and Elgin 2000

In the paper

“These studies place Bmi1, and thereby epigenetic gene regulation, central to the emerging concept of tumor stem cells, which aside from having escaped cellular growth control mechanisms such as the p53 and the pRB pathways, also have (re)instigated a stem cell-like transcription program that allows for continuous self-renewal (Pardal et al. 2003;Valk-Lingbeek et al. 2004).”

What the sources say

• Not checked yetcites Pardal et al. 2003
• Not checked yetcites Valk-Lingbeek et al. 2004

In the paper

“CENP-A was recently found to be overexpressed and mislocalized in primary human colorectal tumors, suggesting a link between CENP-A deregulation and aneuploidy (Tomonaga et al. 2003).”

What the sources say

• Not checked yetcites Tomonaga et al. 2003

In the paper

“the expression of HP1␣ is reportedly down-regulated in invasive human breast cancer cells, and overexpression of HP1␣ results in diminished invasive potential (Kirschmann et al. 2000).”

What the sources say

• Not checked yetcites Kirschmann et al. 2000

In the paper

“Loss of Suv39h in mice results in the displacement of HP1 proteins from pericentromeric heterochromatin, resulting in anaploidy and cancer (Peters et al. 2001).”

What the sources say

• Not checked yetcites Peters et al. 2001