M5L5 Targeting epigenetic mechanisms in cancer therapy

  • DNMT inhibitors - nucleoside analogues (5’azacytidine and 5-2’ decitabine) and non nucleoside analogues (procainamide)

  • RNA can be methylated by different marks - N6-methyladenosine most common, requires METTL3/14

    • METTL3 —> oncogenic targets eg MYC, EGFR upregulation

  • Histone variant H3.3

    • Mutations identified in H3F3A and H3F3B encoding histone variant H3.3

    • First oncohistone

    • Recurrent mutations affecting K21 and G34

  • Chromatin remodelers use ATP to slide or eject nucleosodes

    • Eg SWI/SNF family (eg BAF, pBAF), ISWI, CHD…

    • SWI/SNF mutated in ~20% of most cancer types

  • Histone modifications

    • Writers - HMT, HAT, Ub ligases

    • Readers - PWWP domains, bromodomains, chromodomains

    • Erasers - KDMs, HDACs

  • Acetylation

    • HATs eg GCN5, P300, CBP, Tip60

    • Adds acetyl group which neutralises pos charge of lysine —> relaxed chromatin structure

    • Irregularities —> cancer

    • 4 classes of HDACs, including HDAC1-10 and SIRT1-7

    • HDAC inhibition —> open chromatin, gene expression, may reactivate silenced tumour suppressors

  • Methylation

    • KMTs are highly mutated across cancers

    • Gain of function mutation

  • Key determinant of altered methylation - hypoxia

    • DNA and histone demethylases are dioxygenases - requiring oxygen to work

    • Hypoxia blocks TET demethylase and KDMs blockingf CpG and histone demethylation

    • Blocks cell differentiation —> promotes tumorigenesis

  • Oncometabolites affect DNA and histone methylation

    • Isocitrate dehydrogenase (IDH) converts isocitrate to alpha ketoglutarate in Krebs cycle

    • IDH gain of function converts alpha-KG to 2-hydroxyglutarate (G2HG) which competitively inhibits alpha-KG substrates, driving cancer as a-KG is needed by TET and KDM for demethylation

  • IDH1 and IDH2 inhibitors developed

  • Targeting H3K36me3 deficient cancers

    • SETD2 is an HMT specific for H3K36 trimethylation

    • KDM4A can reverse trimethylation (could be upregulated in cancers)

    • SETD2 mutated in many cancers (tumour suppressor role)

    • H3.3 can inhibit H3K36me3

    • SETD2 is synthatic lethal with Wee1 in fission yeast

    • Ribonucleotide reductase (RRM2) levels are reduced when Wee1 is inhibited

    • RRM2 is degraded by Cdk1 in G2 phase due to its phosphorylation at Thr33 and subsequent ubiquitination

    • Wee1 loss leads to increased dNTP demand but SETD2 loss reduces dNTP supply