Epigenomic alterations in cancer: mechanisms and therapeutic potential

Jaimie S. Gray; Sajad A. Wani; Moray J. Campbell

doi:10.1042/cs20210449

journal article Apr 01, 2022

Epigenomic alterations in cancer: mechanisms and therapeutic potential

Jaimie S. Gray Sajad A. Wani Moray J. Campbell

Clinical Science Vol. 136 No. 7 pp. 473-492 · Portland Press Ltd.

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Abstract

Abstract
The human cell requires ways to specify its transcriptome without altering the essential sequence of DNA; this is achieved through mechanisms which govern the epigenetic state of DNA and epitranscriptomic state of RNA. These alterations can be found as modified histone proteins, cytosine DNA methylation, non-coding RNAs, and mRNA modifications, such as N6-methyladenosine (m6A). The different aspects of epigenomic and epitranscriptomic modifications require protein complexes to write, read, and erase these chemical alterations. Reflecting these important roles, many of these reader/writer/eraser proteins are either frequently mutated or differentially expressed in cancer. The disruption of epigenetic regulation in the cell can both contribute to cancer initiation and progression, and increase the likelihood of developing resistance to chemotherapies. Development of therapeutics to target proteins involved in epigenomic/epitranscriptomic modifications has been intensive, but further refinement is necessary to achieve ideal treatment outcomes without too many off-target effects for cancer patients. Therefore, further integration of clinical outcomes combined with large-scale genomic analyses is imperative for furthering understanding of epigenomic mechanisms in cancer.

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References

194

[1]

Jenuwein "Translating the Histone Code" Science (2001) 10.1126/science.1063127

[2]

Yao "The roles of microRNAs in epigenetic regulation" Curr. Opin. Chem. Biol. (2019) 10.1016/j.cbpa.2019.01.024

[3]

Bender "DNA methylation and epigenetics" Annu. Rev. Plant Biol. (2004) 10.1146/annurev.arplant.55.031903.141641

[4]

Yang "Dynamic transcriptomic m6A decoration: writers, erasers, readers and functions in RNA metabolism" Cell Res. (2018) 10.1038/s41422-018-0040-8

[5]

Hong "Epigenetic age acceleration of stomach adenocarcinoma associated with tumor stemness features, immunoactivation, and favorable prognosis" Front. Genet. (2021) 10.3389/fgene.2021.563051

[6]

Roberts "Epigenetic age and the risk of incident atrial fibrillation" Circulation (2021) 10.1161/circulationaha.121.056456

[7]

Peterson "Histones and histone modifications" Cell (2004) 10.1016/j.cub.2004.07.007

[8]

Hansen "Conformational dynamics of the chromatin fiber in solution: determinants, mechanisms, and functions" Annu. Rev. Biophys. Biomol. (2002) 10.1146/annurev.biophys.31.101101.140858

[9]

Crystal structure of the nucleosome core particle at 2.8 Å resolution

Karolin Luger, Armin W. Mäder, Robin K. Richmond et al.

Nature 1997 10.1038/38444

[10]

Brown "Heterochromatin" Science (80-) (1966) 10.1126/science.151.3709.417

[11]

Huisinga "The contradictory definitions of heterochromatin: transcription and silencing" Chromosoma (2006) 10.1007/s00412-006-0052-x

[12]

Chereji "Functional roles of nucleosome stability and dynamics" Brief. Funct. Genomics (2015) 10.1093/bfgp/elu038

[13]

Clark "Electrostatic mechanism of chromatin folding" J. Mol. Biol. (1990) 10.1016/0022-2836(90)90081-v

[14]

Bannister "Regulation of chromatin by histone modifications" Nature (2011) 10.1038/cr.2011.22

[15]

Huang "SnapShot: histone modifications" Cell (2014) 10.1016/j.cell.2014.09.037

[16]

Creyghton "Histone H3K27ac separates active from poised enhancers and predicts developmental state" Proc. Natl. Acad. Sci. U.S.A. (2010) 10.1073/pnas.1016071107

[17]

High-Resolution Profiling of Histone Methylations in the Human Genome

Artem Barski, Suresh Cuddapah, Kairong Cui et al.

Cell 2007 10.1016/j.cell.2007.05.009

[18]

Kimura "Histone modifications for human epigenome analysis" J. Hum. Genet. (2013) 10.1038/jhg.2013.66

[19]

Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome

Nathaniel D Heintzman, Rhona K Stuart, Gary Hon et al.

Nature Genetics 2007 10.1038/ng1966

[20]

Turner "Histone acetylation as an epigenetic determinant of long-term transcriptional competence" Cell Mol. Life Sci. (1998) 10.1007/s000180050122

[21]

Gao "Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal" Sci. Signal. (2013) 10.1126/scisignal.2004088

[22]

The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data

Ethan Cerami, Jianjiong Gao, Ugur Dogrusoz et al.

Cancer Discovery 2012 10.1158/2159-8290.cd-12-0095

[23]

Dillon "The SET-domain protein superfamily: protein lysine methyltransferases" Genome Biol. (2005) 10.1186/gb-2005-6-8-227

[24]

Sterner "Acetylation of histones and transcription-related factors" Microbiol. Mol. Biol. Rev. (2000) 10.1128/mmbr.64.2.435-459.2000

[25]

Wolf "The protein arginine methyltransferase family: an update about function, new perspectives and the physiological role in humans" Cell. Mol. Life Sci. (2009) 10.1007/s00018-009-0010-x

[26]

Finkelstein "Methionine metabolism in mammals" J. Nutr. Biochem. (1990) 10.1016/0955-2863(90)90070-2

[27]

Feron "The many metabolic sources of acetyl-CoA to support histone acetylation and influence cancer progression" Ann. Transl. Med. (2019) 10.21037/atm.2019.11.140

[28]

Du "Methyl-CpG-binding domain proteins: readers of the epigenome" Epigenomics (2015) 10.2217/epi.15.39

[29]

Musselman "Towards understanding methyllysine readout" Biochim. Biophys. Acta (2014) 10.1016/j.bbagrm.2014.04.001

[30]

Horton "Enzymatic and structural insights for substrate specificity of a family of jumonji histone lysine demethylases" Nat. Struct. Mol. Biol. (2010) 10.1038/nsmb.1753

[31]

Fang "Human LSD2/KDM1b/AOF1 regulates gene transcription by modulating intragenic H3K4me2 methylation" Mol. Cell (2010) 10.1016/j.molcel.2010.07.008

[32]

D’Oto "Histone demethylases and their roles in cancer epigenetics" J. Med. Oncol. Ther. (2016) 10.35841/medical-oncology.1.2.34-40

[33]

Wang "Role of HDACs in normal and malignant hematopoiesis" Mol. Cancer (2020) 10.1186/s12943-019-1127-7

[34]

Nagarajavel "Global “bootprinting” reveals the elastic architecture of the yeast TFIIIB-TFIIIC transcription complex in vivo" Nucleic Acids Res. (2013) 10.1093/nar/gkt611

[35]

The Biology of Chromatin Remodeling Complexes

Cedric R. Clapier, Bradley R. Cairns

Annual Review of Biochemistry 2009 10.1146/annurev.biochem.77.062706.153223

[36]

Wassef "The multiple facets of PRC2 alterations in cancers" J. Mol. Biol. (2017) 10.1016/j.jmb.2016.10.012

[37]

Margueron "The polycomb complex PRC2 and its mark in life" Nature (2011) 10.1038/nature09784

[38]

Cao "SUZ12 is required for both the histone methyltransferase activity and the silencing function of the EED-EZH2 complex" Mol. Cell (2004) 10.1016/j.molcel.2004.06.020

[39]

Piunti "The roles of Polycomb repressive complexes in mammalian development and cancer" Nat. Rev. Mol. Cell Biol. (2021) 10.1038/s41580-021-00341-1

[40]

Piunti "CATACOMB: an endogenous inducible gene that antagonizes H3K27 methylation activity of Polycomb repressive complex 2 via an H3K27M-like mechanism" Sci. Adv. (2019) 10.1126/sciadv.aax2887

[41]

Mohammad "EZH2 is a potential therapeutic target for H3K27M-mutant pediatric gliomas" Nat. Med. (2017) 10.1038/nm.4293

[42]

Varambally "The polycomb group protein EZH2 is involved in progression of prostate cancer" Nature (2002) 10.1038/nature01075

[43]

Wan "Impaired cell fate through gain-of-function mutations in a chromatin reader" Nature (2020) 10.1038/s41586-019-1842-7

[44]

Erb "Transcription control by the ENL YEATS domain in acute leukaemia" Nature (2017) 10.1038/nature21688

[45]

Wan "ENL links histone acetylation to oncogenic gene expression in acute myeloid leukaemia" Nature (2017) 10.1038/nature21687

[46]

Luo "The super elongation complex (SEC) family in transcriptional control" (2012) 10.1038/nrm3417

[47]

Anzick "AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer" Science (80-) (1997) 10.1126/science.277.5328.965

[48]

Varešlija "Comparative analysis of the AIB1 interactome in breast cancer reveals MTA2 as a repressive partner which silences E-Cadherin to promote EMT and associates with a pro-metastatic phenotype" Oncogene (2021) 10.1038/s41388-020-01606-3

[49]

Wang "MDC1 functionally identified as an androgen receptor co-activator participates in suppression of prostate cancer" Nucleic Acids Res. (2015) 10.1093/nar/gkv394

[50]

He "GATA2 facilitates steroid receptor coactivator recruitment to the androgen receptor complex" Proc. Natl. Acad. Sci. U.S.A. (2014) 10.1073/pnas.1421415111

Showing 50 of 194 references

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Details

Published: Apr 01, 2022
Vol/Issue: 136(7)
Pages: 473-492

Authors

J

Jaimie S. Gray

Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH 43210, U.S.A.

S

Sajad A. Wani

Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH 43210, U.S.A.

M

Moray J. Campbell

Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH 43210, U.S.A.; Biomedical Informatics Shared Resource, The Ohio State University, Columbus, OH 43210, U.S.A.

Cite This Article

Jaimie S. Gray, Sajad A. Wani, Moray J. Campbell (2022). Epigenomic alterations in cancer: mechanisms and therapeutic potential. Clinical Science, 136(7), 473-492. https://doi.org/10.1042/cs20210449

Epigenomic alterations in cancer: mechanisms and therapeutic potential

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