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L3 Epigenetics > Epigenetics and cancer > Flashcards

Epigenetics and cancer Flashcards

1
Q

What is cancer?

A

A wide range of different diseases where cells divide uncontrollably within a tissue and often invade other tissues

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2
Q

Why is cancer so lethal? (2)

A
  • Tumours disrupt the functions of the organs in which they arise and spread to
  • Tumour cells require energy and nutrients to support growth which they get from the diet and other tissues by promoting cachexia through signalling processes that they themselves are less sensitive to
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3
Q

What is cachexia?

A

Tissue wasting

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4
Q

What are the 6 main hallmarks of cancer?

A
  • Self sufficiency in growth signals
  • Evasion of growth suppression
  • Evasion of apoptosis
  • Induction of angiogenesis
  • Induction of invasion and metastasis
  • Acquiring replicative immortality
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5
Q

What are the histological features of cancer cells? (3)

A
  • Large nucleus
  • Hyperchromatic chromatin (strongly staining with haematoxylin)
  • High nucleus:cytoplasm ratio
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6
Q

What are the 2 main types of DNA methylation change in cancer? (2)

A
  • Specific patterns of hypermethylation of CpG islands in the 5’ regions of some genes, many of which are cancer related
  • Global genome hypomethylation (40-60% of CpG methylation instead of the normal 80%)
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7
Q

What is CIMP? (2)

A
  • CpG island methylator phenotype
  • Specific patterns of hypermethylation of CpG islands in the 5’ regions of some genes, many cancer related
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8
Q

How can hypomethylation be identified in cancer cells? (2)

A
  • Treat with HpaII which cleaves unmethylated CpGs
  • Results in generation of different fragments in cancer and normal cells
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9
Q

What happens to CDKN2A in cancer? (4)

A
  • CDKN2A encodes tumour suppressors p14ARF and p16INK4a
  • p14ARF inhibits MDM2 to stabilise p53
  • p16INK4a inhibits CDK4/6 which inhibit Rb
  • CDKN2A is hypermethylated (silenced) in skin cancer to encourage uncontrolled proliferation and inhibition of apoptosis
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10
Q

What happens to BRCA1 in cancer? (3)

A
  • BRCA1 is required for double-strand break repair by homologous recombination
  • Germline mutations plus an acquired mutation results in loss of heterozygosity (classic tumour suppressor)
  • BRCA1 can be silenced by hypermethylation, found frequently in familial ovarian cancer, familial and sporadic breast cancer
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11
Q

What is indicated by DNA hypermethylation at BRCA1 in blood cells?

A

Predisposition to cancer

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12
Q

What is the function of E-cadherin (CDH1)?

A

Mediates cell-cell adhesion to maintain integrity of epithelial sheets

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13
Q

What is indicated by loss of E-cadherin function?

A

Development of invasive and metastatic phenotype (EMT)

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14
Q

What happens to CDH1 in cancer? (3)

A
  • 25-40% of hereditary diffuse gastric carcinomas are heterozygous for germline LOF mutations in CDH1
  • 25% of these cases, second ‘hit’ is not a mutation of CDH1 but CDH1 promoter hypermethylation (silenced, epimutation by hypermethylation)
  • The methylation is targeted to the wildtype allele, the mutant is transcriptionally active but functionally inactive
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15
Q

What is the function of IDH 1/2?

A

Isocitrate dehydrogenases 1 and 2 are required for alpha-keto-glutarate in the TCA cycle which is an essential co-factor for TET demethylases

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16
Q

What happens to IDH1 and 2 in cancer? (3)

A
  • GAIN of function mutants are commonly found in glioblastoma and leukaemia
  • Produce 2-hydroxyglutarate instead of alpha-keto-glutarate which is a competitive inhibitor of TET demethylases (and lysine demethylases)
  • Blocks TET demethylase function resulting in persistent DNA methylation and silencing of tumour suppressor genes
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17
Q

What happens when you mutate IDH1 in mice? (3)

A
  • Splenomegaly due to excessive proliferation of haemopoietic progenitors
  • KI mice have 2 fold genome wide CpG methylation
  • Likely mechanism for increased methylation at promoters which could increase likelihood of tumorigenesis
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18
Q

How are transposable elements (TEs) involved in cancer? (4)

A
  • LINEs (class of TEs) are mostly heavily methylated and transcriptionally silent
  • Some LINEs retain mutagenic activity though many have lost this ability due to acquisition of mutations
  • Transcriptionally active LINEs can cause genomic instability/tumorigenesis by inserting into tumour suppressor genes or causing chromosomal rearrangements which can generate proto-oncogenes
  • DNA hypomethylation can induce LINE transcription and transposition but steps leading to hypomethylation aren’t known
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19
Q

How much of the human genome is made of transposable elements (TEs)?

A

Up to 50%

20
Q

What are LINEs? (3)

A
  • Long interspersed nuclear elements
  • Retrotransposons representing 17% of human genome
  • Transcribe RNA then use reverse transcriptase to reverse transcribe the RNA to DNA and insert it somewhere new
21
Q

What were the first cancer-associated changes to chromatin that were noticed? (2)

A
  • General reductions in DNA methylation (hypOmethylation)
  • Promoter-specific hypERmethylation of cancer-linked genes is also a major hallmark
22
Q

What are epimutations? (2)

A
  • An abnormal change in gene expression caused by modifications to the epigenetic state of a gene rather than changes in the DNA sequence itself
  • Promoter-specific hypermethylation epimutations seen in tumour suppressor genes CDKN2A, BRCA1, CDH1 causing silencing
23
Q

How does tumour progression happen? (3)

A
  • Balance between progenitor cell self-renewal and commitment to differentiation in a tissue is disrupted by genetic and epigenetic defects
  • Selection for genetic and epigenetic changes that enhance clonal expansion of progenitors, impair responses to growth suppression signals and differentiation inducers, facilitate EMT, increase genomic instability and impede DNA repair
  • Disruption to normal tissue homeostasis
24
Q

What happens to methylation in cancer? (3)

A
  • Global DNA hypomethylation which may induce transcription of transposable elements that cause genomic instability
  • DNA hypermethylation at promoters/exons/introns to repress tumour suppressor gene expression
  • Also evidence for increased H3K27 and H3K9 methylation at tumour suppressor genes
25
Q

What is the function of the polycomb (PcG) group proteins? (3)

A
  • Pleiohomeotic in Pho-RC binds to polycomb response elements (PREs) in gene promoters and recruits PRC2 and PRC1
    -Enhancer of zeste (EZH2) in PRC2 methylates H3K27 which allows PRC1 binding via the chromodomain of polycomb (in PRC1)
  • Enables the compaction of chromatin to make it transcriptionally silent
26
Q

What is the mammalian version of enhancer of zeste E(z)?

A

EZH2

27
Q

What happens to enhancer of zeste (EZH2) in cancer? (3)

A
  • Highly expressed in prostate cancer
  • Promotes development of benign prostate cancer to metastatic, hormone refractory prostate cancer
  • Correlates with poorer survival
28
Q

How does EZH2 affect proliferation and invasion in prostate cancer? (2)

A
  • Reduction in proliferation seen after EZH2 siRNA transfection
  • EZH2 siRNA blocks prostate cancer cells invasive ability in in vitro invasion assay of crossing porous matrigel basement membrane
29
Q

What is the impact of removing the SET domain of EZH2? (2)

A
  • SET domain contains the H3K27 methyltransferase activity
  • Removal blocks invasion abilities in breast and prostate cancer cells
30
Q

How is EZH2 linked to E-cadherin (CDH1) in breast cancer? (3)

A
  • EZH2 overexpression causes complete suppression of CDH1 transcription (mutually exclusive)
  • Requires EZH2 SET domain
  • Indicates that benign to invasion transition is mediated by EZH2-dependent transcriptional silencing of E-cadherin/CDH1
31
Q

How can EZH2 be targeted in cancer? (2)

A
  • Inhibition by small molecules i.e. competitive inhibitors of the catalytic active site that mimic S-adenosylmethionine binding but can’t donate methyl groups to H3
  • E.g. tazemetostat now used for epithelial sarcomas with EZH2 overexpression
31
Q

What is tazemetostat?

A

A competitive inhibitory SAM mimic small molecule drug used for epithelial sarcomas with EZH2 overexpression

32
Q

What is the effect of tazemetostat? (3)

A
  • Causes inhibition of tumour growth
  • Reduces H3K27 methylation
  • Dose-dependent effects
33
Q

What happens to the PcG proteins in cancer?

A

Many cancer types show overexpression of one or more components of the PcG complexes PRC1 and PRC2 i.e. useful targets

34
Q

What is the human version of trithorax (TRX) protein? (2)

A
  • MLL (mixed lineage leukaemia)
  • MLL1, 2, 3, 4
35
Q

What is the function of the MLL proteins? (2)

A
  • All have H3K4 histone methyltransferase activity encoded by the C-terminal SET domain
  • All have set of PHD (zinc) fingers that enable recognition of methylated H3K4 residues and propagation of H3K4me using their linked SET domains
36
Q

What makes TRX a ‘writer’ and ‘reader’?

A

Has a SET domain which methylates H3K4 (writer) and PHD fingers which recognise H3K4me2,3 (reader)

37
Q

How is MLL involved in cancer? (3)

A
  • MLL genes involved in chromosomal translocations with over 80 different genes encoding 80 different fusion proteins
  • All of the fusions remove the SET domain
  • The remaining MLL sequence can still interact with its protein partners in chromatin but no interactions are altered because no longer coupled to the H3K4 methylation activity of the MLL SET domain
38
Q

What is the normal function of MLL?

A

Promote haematopoietic progenitor development and differentiation

39
Q

What is the impact of chromosomal translocations of MLL? (2)

A
  • Disrupts normal differentiation of myeloid progenitors into monocytes and macrophages
  • Progenitors continue to self-renew and proliferate rather than differentiate which causes leukaemia
40
Q

What are the best understood fusion proteins caused by MLL translocation? (3)

A
  • MLL-AF9
  • MLL-ENL
  • Both constitutively activate target genes in immature progenitor cells by recruiting H3K79 methyltransferase DOT1L
41
Q

What is the impact of MLL-CBP fusion protein? (3)

A
  • Fuses the MLL N-terminus to CBP (histone acetyltransferase)
  • Causes hyperacetylation of target genes which recruits H3K79 methyltransferase DOT1L
  • Causes constitutive activation of target genes
42
Q

How can DOT1L be targeted in cancer? (3)

A
  • Small molecule inhibitors (like tazemetostat) to inhibit H3K79 methyltransferase activity
  • E.g. pinometostat which resembles SAM but specific to DOT1L (EZH2 for tazemetostat)
  • Prevents tumour growth and inhibits H3K79 methyltransferase activity in rodent-human xenograft models, clinical trials underway
43
Q

What is the function of H3K79 methylation?

A

Regulator of global genome repair processes including homologous recombination

44
Q

How might H3K79 methylation be involved in leukaemia?

A

Aberrant DOT1L-mediated H3K79 methylation may be a trigger for DNA repair/replication/recombination/mutagenesis in leukaemia

L3 Epigenetics (15 decks)

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