Cancer Epigenetics
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Transcript of Cancer Epigenetics
Epigene'cs in cancer Def: Waddington refers as the causal genotypic mechanisms that produce phenotypic effects in the next genera5on a6er mitosis or meiosis (Haig, 2004). Currently, epigene5cs is viewed as all the mechanisms that heritably influence gene expression without any altera5on in the DNA sequence,they can be modified by environmental s5muli. Cancer is a consequence of unchecked prolifera5on and aberrant cell death , caused by inac5va5on of TSG and ac5va5on of oncogene; they can be achieved via gene5cally or epigene5cally. Hallmarks of cancer ELSISTE evading apoptosis limitless replica5ve poten5al self sufficiency in growth signal insensi5vity to an5growth signal sustained angiogenesis 5ssue invasion and metastasis emerging hallmarks-‐ deregula5ng cellular energe5cs,avoiding immune destruc5on enabling character-‐ genome instability and muta5on,tumor promo5ng inflamma5on Aberra'on of epigene5c control seen in cancer -‐ tumor suppressor DNA hypermethyla5on genome wide DNA hypomethyla5on dysregula5on of other epigene5c marks/ modifica5on either over-‐expression or muta5on nuclear architecture — disorganisa5on Nuclear size,Nuclear shape,Ploidy Clinical implica'on of aberrant epigene5c control in cancer -‐ Understanding the mechanism of epigene5c in cancer gave therapeu5c opportunity, inven5on and discovery of key pathway inhibitors responsible for tumorigenesis. Prognosis -‐Specific altera5ons associated with outcome e.g. miR-‐34b/c hypermethyla5on associated with metastasis Diagnos'c -‐ epigene5c altera5on as biomarkers Epigene5cs biomarker can be used as single or global profile. Dis5nguish cancer from normal cells in the same blood sample using cells or tumour DNA(cell-‐free DNA) e.g. tumour vs benign skin, tumour vs normal prostate Iden5fy a specific feature of the cancer detec5on, e.g GSTP hypermethyla5on (prostate cancer) Therapeu'c Inform treatment , preclinical candidate & Therapeu5c predic5on e.g. MGMT hypermethyla5on (glioma) suggests pa5ents won’t respond to chemotherapeu5c agent temozolomide, as MGMT is required to process temozolomide (alkylated agent) into ac5ve form Drugs -‐ DNA methyltransferase inhibitor -‐ HDACi Epigene'c modifica'on INCLUDE DNA methyla'on Type -‐5’methylcytosine, 5’hydroxymethylcytosine on CpG dinucleo5de symmetrical,it may be maintained through cell division.
Enzyme maintained by DNA methyltransferase 1 Effect Role of DNA methyla'on is context dependent; it usually cause gene silencing, on rare occasion it causes ac5va5on Dele5on of Dnmt1 can enhance or suppress tumorigenesis Different tumours have different dependencies: 1. Driven by tumour suppressor hypermethyla5on, then deple5on of DNA methyla5on appears to suppress tumorigenesis 2. Driven by chromosomal instability, then deple5on of DNA methyla5on appears to enhance tumorigenesis Effect of DNA methyla5on deple5on can be stage specific i.e. early vs late in tumorigenesis Tumor suppressor gene hypermethyla'on DNA methyla'on silence TSG in cancer,and hypermethylated gene varies by tumor type. CpG island hypermethyla5on – CIMP (methylator phenotype) • Associated with clinically dis5nct tumours
Epigenetic abnormalities, diagnosis and prognosis
• They are frequently found in heritable cancer. E.g -‐ RB gene in re5noblastoma BRCA in breast cancer MGMT in glioma and colorectal tumors GATA4,5 in gastric cancer and oesophageal cancer Epimuta5on more frequent than gene5c changes (eg. glioma and colon cancer)in some cases,It is an early event in tumorigenesis (colon, gastric and liver cancer) Diagnosis: Iden5fica5on of tumour type e.g. CIMP Prognosis: Hypermethyla5on increases with tumorigenicity. CIMP favourable prognosis High methyla5on poor prognosis in MDS, lung cancer Genome wide hypomethyla'on Site -‐Occur at repeat,CpG promoters,introns,gene desert (RCID) CpG island shores of tumour suppressor genes • ICRs–loss of imprin5ng Mechanisms A. Contribute tumorigenesis by increased genomic instability by chromosome rearrangement and mobilisa5on of retrotransposons E.g. Muta5on in DNMT3b cause chromosomal instability B. Ac5va5ng restricted no of t/s specific genes,imprinted genes and miRNA E.g. KRas ac5va5on in gastric cancer IGF2 -‐loss of methyla5on in Wilm’s tumor PosPransla'onal histone modifica'on Type histone methyla5on by lysine and arginine methyltransferase enzymes histone acetyla5on by HAT and HDAC ubiqui5na5on by E1 ,E2 and E3 phosphoryla5on by kinase and phosphorylase Site The modifica5on usually take place on the N-‐terminal regions and surface areas of core histone. H3K7 me2/3 Ac5ve gene H3K4me2/3 Inac5ve gene 4 9 27 Histone acetyla5on H3K9 me2/3 H3K27 me2/3 DNA methyla5on !Effect Modified histone tail act as a docking sites for other chroma5n protein. Beside the enzymes that involved in histone modifica5ons , nucleosome and chromosome remodelling protein par5cipate in epigene5cs control. They affect by influencing nucleosome stability, s5mulate or inhibit TF binding or recruitment for gene expression. In cancer Tumor suppressor gene show loss of ac5ve marks H3K4 acetyla5on,H3K7 me3, gain of inac5ve marks H3K4 me3, H3K27 me3 . Histone modifica5on collaborate with DNA methyla5on changes. cause long range silencing in cancer cells. Muta'ons in histones and histone variants Muta5ons in H3.1 (canonical H3) and histone variant H3.3 very recently iden5fied in childhood high grade glioma (not adult, not low grade) DNMT inhibitor -‐ irreversibly bind DNMTs, a6er they incorporate into DNA. an5neoplas5c effect on low dose, toxicity on high dose HDAC inhibitor -‐ effec5ve against lymphoid malignancy, but non selec5ve targe5ng. Targe5ng on Protein-‐Proteins interac5on domains :Non-‐enzyma5c epigene5c regulators (chroma5n readers) Noncodiing RNA long noncoding RNA -‐ most common transcript in cell, >200nt, act in cis /trans manner miRNA -‐ 22nt RNA bind with 3’ UTR of mRNA, form RISC forma5on, inhibit transla5on siRNA -‐ 20-‐24 nt long and via RISC/RITS forma5on cause gene silencing piRNA expression is deregulated in cancer miRNA dysregula'on Frequently mis-‐expressed in cancer,o6en silenced but s/t ac5vated. Role in cancer depend on targets e.g mi15,16 target pro survival protein BCL-‐2 are silenced in CLL. Let 7 target RAS, silenced in lung Ca miR21 target PTEN, up-‐regulated in glioblastoma Enzymes involved in miRNA and siRNA processing pathway such as DROSHA and DICER are dysregulated in some cancer. LncRNA in cancer HOTAIR act in trans manner, bind with PRC2 & LSD2 (demethylase) over expressed in breast cancer. Prognos5cs :HOTAIR also poor prognos5c indicator in esophageal cancer, also upregulated in colon and liver cancer. Diagnos5cs :PCA3 in prostate cancer, urine test
Therapeu5cs : long noncoding RNAs can be knocked down in vivo for therapy ! !!!!!!!!!!!!!Def: Aberra'on of epigene5c control Chroma'n state Epigene'c modifica'on -‐ DNA methyla'on PosPransla'onal histone modifica'on Noncodiing RNA Cancer Tumor suppressor gene hypermethyla'on -‐site,e.g. Genome wide hypomethyla'on -‐site,mechanisms Histone modifica'on error miRNA dysregula'on LncRNA in cancer
Myelodysplastic syndrome progressed to AML
Cutaneous T cell lymphoma