Molecular Basis of Epigenetic Regulation in Cancer Diagnosis and Treatment

Flashcards generated from lecture notes on the molecular basis of epigenetic regulation in cancer diagnosis and treatment.

Epigenetics

Alteration of gene expression without changing the DNA sequence.

Writers (epigenetics)

Enzymes that participate in chemical addition to DNA or histones.

Erasers (epigenetics)

Enzymes involved in removing chemical tags from DNA or histones.

Readers (epigenetics)

Enzymes that interpret chemical modifications to DNA or histones.

DNA Hypermethylation

Process where methylation occurs at cytosine bases in the promoter region of genes, leading to decreased gene expression.

DNA Hypomethylation

Overall decrease in methylation levels compared to normal cells, affecting intergenic and intronic regions, leading to chromosomal instability.

DNA Methyltransferases (DNMTs)

Enzymes that convert cytosine residues to 5-methylcytosine, leading to transcriptional suppression.

RNA Methylation

Modification of RNA that results in mRNA localization and transcript degradation.

N6-methyladenosine (m6A)

Most abundant RNA modification recognized by RNA binding proteins, affecting mRNA function.

Histone Modification

Takes place at the amino-terminal tail of histones via acetylation, methylation, phosphorylation, ADP-ribosylation, or ubiquitination.

Histone Acetyltransferases (HATs), Histone Methyltransferases (HMTs), Histone Kinases

Add acetyl, methyl, phosphate groups, acting as transcriptional co-activators.

Histone Deacetylases (HDACs), Histone Demethylases (HDMs), Phosphatases

Function as transcriptional co-repressors by removing groups from histone ends.

ATP Dependent Chromatin Remodelling

Modify DNA nucleosome interactions through histone ejection/removal/incorporation via ATP hydrolysis.

Chromatin-remodelling Complexes

Chromatin-remodelling complexes classified into SWI/SNF, CHD, ISWI, and INO80 complexes.

SWI/SNF Complexes

ATP dependent chromatin remodelling complexes mutated in 25% of human cancers.

ISWI complex

Mobilizes nucleosomes, helping transcription factors bind nucleosome-free DNA.

PCA3 and ncRNA

Higher expression has been extensively reported in blood samples of 95% of prostate cancer patients.

PROGENSA™

Quantifies PCA3 expression ratio normalized as input control for prostate specific antigen (PSA) mRNA, used for early detection of prostate cancer.

MGMT gene

Promoter hypermethylation which correlates with favorable treatment outcomes in glioblastoma patients treated with temozolomide.

CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS126

Genes whose methylation status may identify CpG island methylator phenotype (CIMP) positive colon cancers.

VIM, GDF15, and TMEFF2

Show 94% sensitivity and 100% specificity in urine samples for bladder cancer detection.

Enhancer of zeste homolog 2(EZH2)

Participates in histone-methylation and transcriptional repression; significantly reduced expression of histone in breast cancer.

Protein Arginine Methyltransferase (PRMT1)

A histone modifying enzyme which plays an important role in the epithelial-to-mesenchymal transformation (EMT) of breast cancer cells

SETD7

Lysine methyl transferase involved in post translational modification of non-histone protein.

Apoptosis antigen 1 expression

Loss impacts drug resistance, mediated by histone deacetylase 1 (HDAC1) in chemoresistant ovarian cancer cells.

H3K27me3 and H3K4me3 methyltransferases

Showed that these genes are involved in epigenetic silencing during chemotherapies and are prone to hypermethylation.

Epigenetic inhibitors for combinational therapies

Effective by repair of pathways associated with drug response for chemo- desensitization of resistant tumors.

Epidrugs

Inhibitors of DNA methyltransferase (DNMTi) and histone deacetylase (HDACi) enzymes.

5-azacitidine (Azacitidine)

First US-FDA approved epigenetic drug, a DNMTi, used in treatment of myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML).

Tazemetostat

Inhibitor of EZH2 approved by US-FDA in June 2020 for treating adult patients with relapsed or follicular lymphoma with EZH2 positive mutations.

Pinometostat

Inhibitor of the histone methyltransferase DOT1L, which specifically kills the MLL-fusion leukaemia cells.

GSK2879552

Inhibitor of lysine-specific histone demethylase 1A (LSD1) used in the treatment of lung cancer with a specific DNA hypomethylation.

Epi proLung®

Assay that has received the Conformité Européenne (CE) mark as In Vitro Diagnostic (IVD) test for lung cancer diagnosis, based on methylation analysis of SHOX2 and PTGER4 genes.

miRpredX-31-3p kit

Based on the quantification of miR-31-3p expression levels and is used to recognise metastatic colorectal cancer patients who can benefit from anti-EGFR (epidermal growth factor receptor) therapy

Integrated Network Medicine

Analytical methods like protein-protein interaction (PPI) networks, correlation-based networks and gene regulatory networks utilized to roll out key genes, relevant regulatory and co- regulatory networks in causing disease pathogenesis

Genomic Regions Enrichment of Annotations Tool (GREAT)

Tool for functional enrichment analysis of DNA binding events across the entire genome, identifying gene-regulatory networks and subnetworks in epigenomics data analysis.

Functional Epigenetic Modules (FEM)

Integrative epigenome-transcriptome-interactome tool that identified HAND2 methylation as an important epigenetic alteration in the development of endometrium cancer.

Epigenetic Module based on Differential Networks (EMDN)

Algorithm that performs integrative analysis on epigenetic modifications and their effect on gene expression.

Deep Neural Network (DNN)

Algorithm used to predict cancer diagnosis in the DNA methylation data

Weighted Correlation Network Analysis (WGCNA)

Analysis of 201 patients in a TCGA prostate cancer dataset revealed hypermethylation of FOXD1 might promote poor prognosis

SWItchMiner (SWIM)

Tool used to identify potential therapeutic targets when applied to large panel of cancer datasets from TCGA.