Regulation of transcription in cancer#Transcription silencing/activation in cancers

In humans, about 70% of promoters located near the transcription start site of a gene (proximal promoters) contain a CpG island.{{cite journal |vauthors=Saxonov S, Berg P, Brutlag DL |title=A genome-wide analysis of CpG dinucleotides in the human genome distinguishes two distinct classes of promoters |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=103 |issue=5 |pages=1412–1417 |year=2006 |pmid=16432200 |pmc=1345710 |doi=10.1073/pnas.0510310103 |bibcode=2006PNAS..103.1412S |doi-access=free }}{{cite journal |vauthors=Deaton AM, Bird A |title=CpG islands and the regulation of transcription |journal=Genes Dev. |volume=25 |issue=10 |pages=1010–1022 |year=2011 |pmid=21576262 |pmc=3093116 |doi=10.1101/gad.2037511 }} CpG islands are generally 200 to 2000 base pairs long, have a C:G base pair content >50%, and have regions of DNA where a cytosine nucleotide is followed by a guanine nucleotide and this occurs frequently in the linear sequence of bases along its 5′ → 3′ direction.{{cite journal |vauthors=Okugawa Y, Grady WM, Goel A |title=Epigenetic Alterations in Colorectal Cancer: Emerging Biomarkers |journal=Gastroenterology |volume=149 |issue=5 |pages=1204–1225.e12 |year=2015 |pmid=26216839 |pmc=4589488 |doi=10.1053/j.gastro.2015.07.011 }}{{cite journal |vauthors=Gardiner-Garden M, Frommer M |title=CpG islands in vertebrate genomes |journal=J. Mol. Biol. |volume=196 |issue=2 |pages=261–282 |year=1987 |pmid=3656447 |doi= 10.1016/0022-2836(87)90689-9}}

Genes may also have distant promoters (distal promoters) and these frequently contain CpG islands as well. An example is the promoter of the DNA repair gene ERCC1, where the CpG island-containing promoter is located about 5,400 nucleotides upstream of the coding region of the ERCC1 gene.{{cite journal |vauthors=Chen HY, Shao CJ, Chen FR, Kwan AL, Chen ZP |title=Role of ERCC1 promoter hypermethylation in drug resistance to cisplatin in human gliomas |journal=Int. J. Cancer |volume=126 |issue=8 |pages=1944–1954 |year=2010 |pmid=19626585 |doi=10.1002/ijc.24772 |s2cid=3423262 |doi-access=free }} CpG islands also occur frequently in promoters for functional noncoding RNAs such as microRNAs.{{cite book |vauthors=Kaur S, Lotsari-Salomaa JE, Seppänen-Kaijansinkko R, Peltomäki P |chapter=MicroRNA Methylation in Colorectal Cancer |title=Non-coding RNAs in Colorectal Cancer |volume=937 |pages=109–122 |year=2016 |pmid=27573897 |doi=10.1007/978-3-319-42059-2_6 |series=Advances in Experimental Medicine and Biology |isbn=978-3-319-42057-8 }}

In humans, DNA methylation occurs at the 5′ position of the pyrimidine ring of the cytosine residues within CpG sites to form 5-methylcytosines. The presence of multiple methylated CpG sites in CpG islands of promoters causes stable inhibition (silencing) of genes.{{cite journal |vauthors=Bird A |title=DNA methylation patterns and epigenetic memory |journal=Genes Dev. |volume=16 |issue=1 |pages=6–21 |year=2002 |pmid=11782440 |doi=10.1101/gad.947102 |doi-access=free }} Silencing of transcription of a gene may be initiated by other mechanisms, but this is often followed by methylation of CpG sites in the promoter CpG island to cause the stable silencing of the gene.

{{further|DNA methylation in cancer}}

In cancers, loss of expression of genes occurs about 10 times more frequently by transcription silencing (caused by promoter hypermethylation of CpG islands) than by mutations. As Vogelstein et al. point out, in a colorectal cancer there are usually about 3 to 6 driver mutations and 33 to 66 hitchhiker or passenger mutations.{{cite journal |vauthors=Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA, Kinzler KW |title=Cancer genome landscapes |journal=Science |volume=339 |issue=6127 |pages=1546–1558 |year=2013 |pmid=23539594 |pmc=3749880 |doi=10.1126/science.1235122 |bibcode=2013Sci...339.1546V }} In contrast, in colon tumors compared to adjacent normal-appearing colonic mucosa, there are about 600 to 800 heavily methylated CpG islands in promoters of genes in the tumors while these CpG islands are not methylated in the adjacent mucosa.{{cite journal |vauthors=Illingworth RS, Gruenewald-Schneider U, Webb S, Kerr AR, James KD, Turner DJ, Smith C, Harrison DJ, Andrews R, Bird AP |title=Orphan CpG islands identify numerous conserved promoters in the mammalian genome |journal=PLOS Genet. |volume=6 |issue=9 |pages=e1001134 |year=2010 |pmid=20885785 |pmc=2944787 |doi=10.1371/journal.pgen.1001134 |doi-access=free }}{{cite journal |vauthors=Wei J, Li G, Dang S, Zhou Y, Zeng K, Liu M |title=Discovery and Validation of Hypermethylated Markers for Colorectal Cancer |journal=Dis. Markers |volume=2016 |page=2192853 |year=2016 |pmid=27493446 |pmc=4963574 |doi=10.1155/2016/2192853 |doi-access=free }}{{cite journal |vauthors=Beggs AD, Jones A, El-Bahrawy M, El-Bahwary M, Abulafi M, Hodgson SV, Tomlinson IP |title=Whole-genome methylation analysis of benign and malignant colorectal tumours |journal=J. Pathol. |volume=229 |issue=5 |pages=697–704 |year=2013 |pmid=23096130 |pmc=3619233 |doi=10.1002/path.4132 }}

Using gene set enrichment analysis, 569 out of 938 gene sets were hypermethylated and 369 were hypomethylated in cancers. Hypomethylation of CpG islands in promoters results in increased transcription of the genes or gene sets affected.

One study{{cite journal |vauthors=Schnekenburger M, Diederich M |title=Epigenetics Offer New Horizons for Colorectal Cancer Prevention |journal=Curr Colorectal Cancer Rep |volume=8 |issue=1 |pages=66–81 |year=2012 |pmid=22389639 |pmc=3277709 |doi=10.1007/s11888-011-0116-z }} listed 147 specific genes with colon cancer-associated hypermethylated promoters and 27 with hypomethylated promoters, along with the frequency with which these hyper/hypo-methylations were found in colon cancers. At least 10 of those genes had hypermethylated promoters in nearly 100% of colon cancers. They also indicated 11 microRNAs whose promoters were hypermethylated in colon cancers at frequencies between 50% and 100% of cancers. MicroRNAs (miRNAs) are small endogenous RNAs that pair with sequences in messenger RNAs to direct post-transcriptional repression. On average, each microRNA represses or inhibits transcriptional expression of several hundred target genes. Thus microRNAs with hypermethylated promoters may be allowing enhanced transcription of hundreds to thousands of genes in a cancer.{{cite journal |vauthors=Friedman RC, Farh KK, Burge CB, Bartel DP |title=Most mammalian mRNAs are conserved targets of microRNAs |journal=Genome Res. |volume=19 |issue=1 |pages=92–105 |year=2009 |pmid=18955434 |pmc=2612969 |doi=10.1101/gr.082701.108 }}

For more than 20 years, microRNAs have been known to act in the cytoplasm to degrade transcriptional expression of specific target gene messenger RNAs (see microRNA history). However, recently, Gagnon et al.{{cite journal |vauthors=Gagnon KT, Li L, Chu Y, Janowski BA, Corey DR |title=RNAi factors are present and active in human cell nuclei |journal=Cell Rep |volume=6 |issue=1 |pages=211–221 |year=2014 |pmid=24388755 |pmc=3916906 |doi=10.1016/j.celrep.2013.12.013 }} showed that as many as 75% of microRNAs may be shuttled back into the nucleus of cells. Some nuclear microRNAs have been shown to mediate transcriptional gene activation or transcriptional gene inhibition.{{cite journal |vauthors=Catalanotto C, Cogoni C, Zardo G |title=MicroRNA in Control of Gene Expression: An Overview of Nuclear Functions |journal=Int J Mol Sci |volume=17 |issue=10 |page= 1712|year=2016 |pmid=27754357 |doi=10.3390/ijms17101712 |pmc=5085744|doi-access=free }}

DNA repair genes are frequently repressed in cancers due to hypermethylation of CpG islands within their promoters. In head and neck squamous cell carcinomas at least 15 DNA repair genes have frequently hypermethylated promoters; these genes are XRCC1, MLH3, PMS1, RAD51B, XRCC3, RAD54B, BRCA1, SHFM1, GEN1, FANCE, FAAP20, SPRTN, SETMAR, HUS1, and PER1.{{cite journal |vauthors=Rieke DT, Ochsenreither S, Klinghammer K, Seiwert TY, Klauschen F, Tinhofer I, Keilholz U |title=Methylation of RAD51B, XRCC3 and other homologous recombination genes is associated with expression of immune checkpoints and an inflammatory signature in squamous cell carcinoma of the head and neck, lung and cervix |journal=Oncotarget |volume= 7|issue= 46|pages= 75379–75393|year=2016 |pmid=27683114 |doi=10.18632/oncotarget.12211 |pmc=5342748 }} About seventeen types of cancer are frequently deficient in one or more DNA repair genes due to hypermethylation of their promoters.{{cite book |vauthors=Jin B, Robertson KD |chapter=DNA Methyltransferases, DNA Damage Repair, and Cancer |title=Epigenetic Alterations in Oncogenesis |volume=754 |pages=3–29 |year=2013 |pmid=22956494 |pmc=3707278 |doi=10.1007/978-1-4419-9967-2_1 |series=Advances in Experimental Medicine and Biology |isbn=978-1-4419-9966-5 }} As summarized in one review article, promoter hypermethylation of the DNA repair gene MGMT occurs in 93% of bladder cancers, 88% of stomach cancers, 74% of thyroid cancers, 40%-90% of colorectal cancers and 50% of brain cancers.{{Citation needed|date=December 2019|reason=removed citation to predatory publisher content}} Promoter hypermethylation of LIG4 occurs in 82% of colorectal cancers. This review article also indicates promoter hypermethylation of NEIL1 occurs in 62% of head and neck cancers and in 42% of non-small-cell lung cancers; promoter hypermetylation of ATM occurs in 47% of non-small-cell lung cancers; promoter hypermethylation of MLH1 occurs in 48% of squamous cell carcinomas; and promoter hypermethylation of FANCB occurs in 46% of head and neck cancers.{{Citation needed|date=December 2019|reason=removed citation to predatory publisher content}}

On the other hand, the promoters of two genes, PARP1 and FEN1, were hypomethylated and these genes were over-expressed in numerous cancers. PARP1 and FEN1 are essential genes in the error-prone and mutagenic DNA repair pathway microhomology-mediated end joining. If this pathway is over-expressed, the excess mutations it causes can lead to cancer. PARP1 is over-expressed in tyrosine kinase-activated leukemias,{{cite journal |vauthors=Muvarak N, Kelley S, Robert C, Baer MR, Perrotti D, Gambacorti-Passerini C, Civin C, Scheibner K, Rassool FV |title=c-MYC Generates Repair Errors via Increased Transcription of Alternative-NHEJ Factors, LIG3 and PARP1, in Tyrosine Kinase-Activated Leukemias |journal=Mol. Cancer Res. |volume=13 |issue=4 |pages=699–712 |year=2015 |pmid=25828893 |doi=10.1158/1541-7786.MCR-14-0422 |pmc=4398615}} in neuroblastoma,{{cite journal |vauthors=Newman EA, Lu F, Bashllari D, Wang L, Opipari AW, Castle VP |title=Alternative NHEJ Pathway Components Are Therapeutic Targets in High-Risk Neuroblastoma |journal=Mol. Cancer Res. |volume=13 |issue=3 |pages=470–482 |year=2015 |pmid=25563294 |doi=10.1158/1541-7786.MCR-14-0337 |doi-access=free }} in testicular and other germ cell tumors,{{cite journal |vauthors=Mego M, Cierna Z, Svetlovska D, Macak D, Machalekova K, Miskovska V, Chovanec M, Usakova V, Obertova J, Babal P, Mardiak J |title=PARP expression in germ cell tumours |journal=J. Clin. Pathol. |volume=66 |issue=7 |pages=607–612 |year=2013 |pmid=23486608 |doi=10.1136/jclinpath-2012-201088 |s2cid=535704 }} and in Ewing's sarcoma,{{cite journal |vauthors=Newman RE, Soldatenkov VA, Dritschilo A, Notario V |title=Poly(ADP-ribose) polymerase turnover alterations do not contribute to PARP overexpression in Ewing's sarcoma cells |journal=Oncol. Rep. |volume=9 |issue=3 |pages=529–532 |year=2002 |pmid=11956622 |doi= 10.3892/or.9.3.529}} FEN1 is over-expressed in the majority of cancers of the breast,{{cite journal |vauthors=Singh P, Yang M, Dai H, Yu D, Huang Q, Tan W, Kernstine KH, Lin D, Shen B |title=Overexpression and hypomethylation of flap endonuclease 1 gene in breast and other cancers |journal=Mol. Cancer Res. |volume=6 |issue=11 |pages=1710–1717 |year=2008 |pmid=19010819 |pmc=2948671 |doi=10.1158/1541-7786.MCR-08-0269 }} prostate,{{cite journal |vauthors=Lam JS, Seligson DB, Yu H, Li A, Eeva M, Pantuck AJ, Zeng G, Horvath S, Belldegrun AS |title=Flap endonuclease 1 is overexpressed in prostate cancer and is associated with a high Gleason score |journal=BJU Int. |volume=98 |issue=2 |pages=445–451 |year=2006 |pmid=16879693 |doi=10.1111/j.1464-410X.2006.06224.x |s2cid=22165252 }} stomach,{{cite journal |vauthors=Kim JM, Sohn HY, Yoon SY, Oh JH, Yang JO, Kim JH, Song KS, Rho SM, Yoo HS, Yoo HS, Kim YS, Kim JG, Kim NS |title=Identification of gastric cancer-related genes using a cDNA microarray containing novel expressed sequence tags expressed in gastric cancer cells |journal=Clin. Cancer Res. |volume=11 |issue=2 Pt 1 |pages=473–482 |year=2005 |doi=10.1158/1078-0432.473.11.2 |pmid=15701830 |doi-access=free }}{{cite journal |vauthors=Wang K, Xie C, Chen D |title=Flap endonuclease 1 is a promising candidate biomarker in gastric cancer and is involved in cell proliferation and apoptosis |journal=Int. J. Mol. Med. |volume=33 |issue=5 |pages=1268–1274 |year=2014 |pmid=24590400 |doi=10.3892/ijmm.2014.1682 |doi-access=free }} neuroblastomas,{{cite journal |vauthors=Krause A, Combaret V, Iacono I, Lacroix B, Compagnon C, Bergeron C, Valsesia-Wittmann S, Leissner P, Mougin B, Puisieux A |title=Genome-wide analysis of gene expression in neuroblastomas detected by mass screening |journal=Cancer Lett. |volume=225 |issue=1 |pages=111–120 |year=2005 |pmid=15922863 |doi=10.1016/j.canlet.2004.10.035 |s2cid=44644467 |url=https://hal.archives-ouvertes.fr/hal-00157917/file/Cancer_Letters_2004.pdf}} pancreatic,{{cite journal |vauthors=Iacobuzio-Donahue CA, Maitra A, Olsen M, Lowe AW, van Heek NT, Rosty C, Walter K, Sato N, Parker A, Ashfaq R, Jaffee E, Ryu B, Jones J, Eshleman JR, Yeo CJ, Cameron JL, Kern SE, Hruban RH, Brown PO, Goggins M |title=Exploration of global gene expression patterns in pancreatic adenocarcinoma using cDNA microarrays |journal=Am. J. Pathol. |volume=162 |issue=4 |pages=1151–1162 |year=2003 |pmid=12651607 |pmc=1851213 |doi=10.1016/S0002-9440(10)63911-9 }} and lung.{{cite journal |vauthors=Nikolova T, Christmann M, Kaina B |title=FEN1 is overexpressed in testis, lung and brain tumors |journal=Anticancer Res. |volume=29 |issue=7 |pages=2453–2459 |year=2009 |pmid=19596913 }}

DNA damage appears to be the primary underlying cause of cancer.{{cite journal |vauthors=Kastan MB |title=DNA damage responses: mechanisms and roles in human disease: 2007 G.H.A. Clowes Memorial Award Lecture |journal=Mol. Cancer Res. |volume=6 |issue=4 |pages=517–524 |year=2008 |pmid=18403632 |doi=10.1158/1541-7786.MCR-08-0020 |doi-access=free }}{{cite book |last1= Bernstein |first1=C |last2=Prasad |first2=AR |last3=Nfonsam |first3=V |last4=Bernstein |first4=H. |year=2013 |chapter= Chapter 16: DNA Damage, DNA Repair and Cancer |title= New Research Directions in DNA Repair |editor-first=Clark |editor-last=Chen | location = Rijeka | isbn=978-953-51-1114-6|page=413}} If accurate DNA repair is deficient, DNA damages tend to accumulate. Such excess DNA damage can increase mutational errors during DNA replication due to error-prone translesion synthesis. Excess DNA damage can also increase epigenetic alterations due to errors during DNA repair. Such mutations and epigenetic alterations can give rise to cancer (see malignant neoplasms). Thus, CpG island hyper/hypo-methylation in the promoters of DNA repair genes are likely central to progression to cancer.{{cite journal |vauthors=O'Hagan HM, Mohammad HP, Baylin SB |title=Double strand breaks can initiate gene silencing and SIRT1-dependent onset of DNA methylation in an exogenous promoter CpG island |journal=PLOS Genetics |volume=4 |issue=8 |pages=e1000155 |year=2008 |pmid=18704159 |pmc=2491723 |doi=10.1371/journal.pgen.1000155 |doi-access=free }}{{cite journal |vauthors=Cuozzo C, Porcellini A, Angrisano T |title=DNA damage, homology-directed repair, and DNA methylation |journal=PLOS Genetics |volume=3 |issue=7 |pages=e110 | date=July 2007 |pmid=17616978 |pmc=1913100 |doi=10.1371/journal.pgen.0030110|display-authors=etal |doi-access=free }}

• Eukaryotic transcription
• Gene expression
• Transcriptional regulation
• Cancer epigenetics

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Category:Gene expression

Category:Non-coding RNA

Category:Epigenetics

Category:Cancer epigenetics

Category:DNA

Category:Medical regulation