lecture 9 - novel targets Flashcards
What is the definition of epigenetics?
Heritable information encoded by modifications to the genome and chromatin
Affect structure and conformation of chromatin, which consequently affects transcription
What are the main epigenetic mechanisms that occur?
Histone acetylation (HATs) and deacetylation (HDACs) - histone acetyl transferases and histone deacetylases
DNA methylation (DNMTs) - generally leads to suppression
What is the role of histone acetylation and what are the different types of chromatin?
Histone proteins contain many basic amino acids with positive charge, which enables integration with negative phosphate backbone of DNA
Acetylation blocks the ability of histones to bind to DNA by masking the negative charge
relaxes interaction of DNA with nucleosome
Heterochromatin - densely packed nucleosomes, condensed, not actively transcribed, deacetylated histones
Euchromatin - extended ‘beads on a string’ appearance, being actively transcribed, acetylated histones
What are the functions of miRNA in cancer and what is one example of an miRNA that represses TSGs?
miRNAs lead to transcriptional repression or mRNA degradation, e.g. p53 promotes lncRNA-p21, leading to repression of genes involved in proliferation and survival
Oncomir - an unregulated miRNA that represses TSGs
miRNAs that regulate oncogenes are themselves tumour suppressors and are lost in cancer
Which genes are targeted by methylation by DNMTs in cancer?
TSGs
How reversal of epigenetic modifications (reactivation of TSGs) be achieved therapeutically?
DNA methylation inhibitors - 5’ modified analogues of deoxycytidine
these can be incorporated into DNA/RNA and block DNMT activity
can cause DNA instability and apoptosis of tumour cells, but methylation returns if drug is stopped
Only effective in leukaemia and not solid tumours
How can apoptosis be triggered in cancer and what is a therapeutic approach to treat it?
chemotherapeutic agents and radiation therapy cause DNA damage and trigger apoptosis
tumour cells have activated caspases that are inhibited by IAPs - they are therefore primed for apoptosis
XIAP inhibitors (polyphenylureas) can be used as a treatment
How do mutations in the extrinsic pathway occur and lead to cancer?
Sunburn causes the death of skin cells due to UV induced DNA damage and apoptosis
This is triggered by FasR clustering and the activation of caspase 8
Mutations in FasR or suppression of caspase expression can lead to loss of apoptosis - this results in accumulation of mutations and can lead to melanoma
loss of caspase expression can be due to: hypermethylation of the promoter, or deletions and missense mutations
how do mutations in the intrinsic pathway occur and lead to cancer?
Mutations in epigenetic regulations (p53, MDM2, BAX, IAPs) - e.g. Bcl-2 - translocation or altered miRNA expression that normally suppresses Bcl2 transcription
Therapeutic approach - HDAC inhibitor (vorinostat) induces expression of pro-apoptotic Bid/Bax
What is the TRAIL pathway and how can it be targeted?
TNF-related apoptosis-inducing ligand, and its death receptors
TRAIl can induce apoptosis, via FADD and caspase 8, in many tumour cells, independently of p53
therapeutic approach - recombinant TRAIL or agonistic Mabs
What are the effects of enhanced metabolic activity in cancer?
reprogramming energy metabolism is another hallmark of cancer - they can carry out aerobic glycolysis (glucose to lactate)
Effects:
enhanced glucose uptake and utilisation
generation of acetyl CoA, which enhances histone acetylation
lactate can activate PI3K and stimulate angiogenesis
glycolysis depletes glucose levels in microenvironment and decreases effector function of tumour infiltrating lymphocytes
