Cancer epigenetics Flashcards
What effects can epigenetic regulation have in cancer?
- turning off growth inhibitory genes
- turning on growth promoting genes
Why are epigenetics of interest in cancer?
- can act as markers of disease
- targets for therapy
by reactivating silenced genes or silencing oncogenes
What happens as a result of p16 inactivation?
- p16 is a CDK inhibitor
- loss of p16 leads to an increase in inactive RB that can no longer bind E2F
- loss of cellular capacity to block cell cycle progression
- can be hypermethylated or genetically inhibited
- sometimes can have both
Give an example of a gene that may be hypermethylated and silenced in cancer (3)
- HOXA5 in breast cancer
- p16 in many solid tumours and lymphoma
- wnt inhibitors can be hypermethylated in colon cancer
Give an example of epigenetic regulation of miRNA
- miR-127 can be silenced by hypermethylation and histone modifications and switched off in cancer
- can be pharmacologically turned back on
- represses BCL6 oncogene activity
How can some tumours such as Wilm’s tumour be analysed for methylation?
- methylated DNA immunoprecipitation chip
- use antibodies that detect methylated DNA with fluorescent labels to see where there are changes between normal and tumour cells
- Wilms tumour has high levels of methylation that can alter imprinting, MET and B-catenin translocation in and out of the nucleus
Describe dysregulated wnt/b-catenin in cancer
- Wnt signalling requires the translocation of b-catenin into the nucleus
- mutations in Wilm’s tumour perhaps as a result of high levels of methylation can allow b-catenin to travel in and out of the nucleus deregulated
- this stops the activity of the destruction complex and allows cell survival
What is long range epigenetic signalling?
- epigenetic modifications on genes can also affect surrounding genes on the chromosome leading to entire inactive regions
- nucleosome spacing
- sequential recruitment
- boundary elements can prevent this or reduce its action
- occurs in colon cancer where DNA methylation on one region leads to the silencing of an entire chromosome band
- neighbourhood level effects
Give an example of how histones themselves can be mutated in cancer
- seen in childhood glioblastoma at H3K27
- mutations can change the lysine to methionine
- OLIG2 is normally repressed at K27 by PCR2
- the mutant form sequesters PCR2 complexes away from the DNA and allows increased OLIG2 transcription
- OLGI2 can interfere with p53
Why is inhibition of TETs conducive to DNA hypermethylation?
- TET is involved in the conversion of methylcytosine into other altered cytosine residues
- TET enzymes require A-KG as a cofactor created in the TCA cycle citrate -> A-KG
- IDH mutations can lower a-KG, lower TET and lead to altered epigenetic regulation
- mutation that confers the new IDH activity -> 2DHG (CMT)
- also often seen in childhood (and adulthood) glioblastoma
How is p53 decreased in breast cancer?
- few p53 mutations in breast cancer
- but p53 expression requires trans-activation by cofactor HOXA5
- HOXA5 is frequently hypermethjylated and silenced in breat cancer
How can hypermethylation and mutation be linked?
- promoter methylation can lead to silencing of repair genes
- non-promoter methylation can lead to spontaneous deamination, enhanced UV uptake and enhanced carcinogen binding
How can epigenetics be used diagnostically?
methylation of p16 can be detected in DNA using PCR up to 3 years before clinical diagnosis of lung cancer
Give an example of a therapy against cancer that targets epigenetics?
- E2H2 histone methylatransferase inhibition by small molecule inhibitors
- used in lymphoma patients with oncogenic point mutations in EZH2
- clinical trials ongoing
- bromodomains can also be inhibited
- DNMT inhibitors
What are bromodomains and how can they be inhibited?
histone writers that recognise acetyl groups and open up the chormatin and modulate gene expression. inhibitors block this interaction where it occurs oncogenically to decrease oncogene activity
