Biology:Regulation of transcription in cancer

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Generally, in progression to cancer, hundreds of genes are silenced or activated. Although silencing of some genes in cancers occurs by mutation, a large proportion of carcinogenic gene silencing is a result of altered DNA methylation (see DNA methylation in cancer). DNA methylation causing silencing in cancer typically occurs at multiple CpG sites in the CpG islands that are present in the promoters of protein coding genes. Altered expressions of microRNAs also silence or activate many genes in progression to cancer (see microRNAs in cancer). Altered microRNA expression occurs through hyper/hypo-methylation of CpG sites in CpG islands in promoters controlling transcription of the microRNAs.

Silencing of DNA repair genes through methylation of CpG islands in their promoters appears to be especially important in progression to cancer (see methylation of DNA repair genes in cancer).

CpG islands in promoters

In humans, about 70% of promoters located near the transcription start site of a gene (proximal promoters) contain a CpG island.[1][2] 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.[3][4]

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.[5] CpG islands also occur frequently in promoters for functional noncoding RNAs such as microRNAs.[6]

Transcription silencing due to methylation of CpG islands

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.[7] 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.[7]

Transcription silencing/activation in cancers

Further information: Biology: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.[8] 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.[9][10][11]

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.[11]

One study[12] 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.[13]

Transcription inhibition and activation by nuclear microRNAs

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.[14] 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.[15]

DNA repair genes with hyper/hypo-methylated promoters in cancers

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.[16] About seventeen types of cancer are frequently deficient in one or more DNA repair genes due to hypermethylation of their promoters.[17] 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] 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]

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,[18] in neuroblastoma,[19] in testicular and other germ cell tumors,[20] and in Ewing's sarcoma,[21] FEN1 is over-expressed in the majority of cancers of the breast,[22] prostate,[23] stomach,[24][25] neuroblastomas,[26] pancreatic,[27] and lung.[28]

DNA damage appears to be the primary underlying cause of cancer.[29][30] 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.[31][32]

See also

References

  1. ↑ "A genome-wide analysis of CpG dinucleotides in the human genome distinguishes two distinct classes of promoters". Proc. Natl. Acad. Sci. U.S.A. 103 (5): 1412–1417. 2006. doi:10.1073/pnas.0510310103. PMID 16432200. Bibcode: 2006PNAS..103.1412S. 
  2. ↑ "CpG islands and the regulation of transcription". Genes Dev. 25 (10): 1010–1022. 2011. doi:10.1101/gad.2037511. PMID 21576262. 
  3. ↑ "Epigenetic Alterations in Colorectal Cancer: Emerging Biomarkers". Gastroenterology 149 (5): 1204–1225.e12. 2015. doi:10.1053/j.gastro.2015.07.011. PMID 26216839. 
  4. ↑ "CpG islands in vertebrate genomes". J. Mol. Biol. 196 (2): 261–282. 1987. doi:10.1016/0022-2836(87)90689-9. PMID 3656447. 
  5. ↑ "Role of ERCC1 promoter hypermethylation in drug resistance to cisplatin in human gliomas". Int. J. Cancer 126 (8): 1944–1954. 2010. doi:10.1002/ijc.24772. PMID 19626585. 
  6. ↑ "MicroRNA Methylation in Colorectal Cancer". Non-coding RNAs in Colorectal Cancer. Advances in Experimental Medicine and Biology. 937. 2016. pp. 109–122. doi:10.1007/978-3-319-42059-2_6. ISBN 978-3-319-42057-8. 
  7. ↑ 7.0 7.1 "DNA methylation patterns and epigenetic memory". Genes Dev. 16 (1): 6–21. 2002. doi:10.1101/gad.947102. PMID 11782440. 
  8. ↑ "Cancer genome landscapes". Science 339 (6127): 1546–1558. 2013. doi:10.1126/science.1235122. PMID 23539594. Bibcode: 2013Sci...339.1546V. 
  9. ↑ "Orphan CpG islands identify numerous conserved promoters in the mammalian genome". PLOS Genet. 6 (9): e1001134. 2010. doi:10.1371/journal.pgen.1001134. PMID 20885785. 
  10. ↑ "Discovery and Validation of Hypermethylated Markers for Colorectal Cancer". Dis. Markers 2016: 2192853. 2016. doi:10.1155/2016/2192853. PMID 27493446. 
  11. ↑ 11.0 11.1 "Whole-genome methylation analysis of benign and malignant colorectal tumours". J. Pathol. 229 (5): 697–704. 2013. doi:10.1002/path.4132. PMID 23096130. 
  12. ↑ "Epigenetics Offer New Horizons for Colorectal Cancer Prevention". Curr Colorectal Cancer Rep 8 (1): 66–81. 2012. doi:10.1007/s11888-011-0116-z. PMID 22389639. 
  13. ↑ "Most mammalian mRNAs are conserved targets of microRNAs". Genome Res. 19 (1): 92–105. 2009. doi:10.1101/gr.082701.108. PMID 18955434. 
  14. ↑ "RNAi factors are present and active in human cell nuclei". Cell Rep 6 (1): 211–221. 2014. doi:10.1016/j.celrep.2013.12.013. PMID 24388755. 
  15. ↑ "MicroRNA in Control of Gene Expression: An Overview of Nuclear Functions". Int J Mol Sci 17 (10): 1712. 2016. doi:10.3390/ijms17101712. PMID 27754357. 
  16. ↑ "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". Oncotarget 7 (46): 75379–75393. 2016. doi:10.18632/oncotarget.12211. PMID 27683114. 
  17. ↑ "DNA Methyltransferases, DNA Damage Repair, and Cancer". Epigenetic Alterations in Oncogenesis. Advances in Experimental Medicine and Biology. 754. 2013. pp. 3–29. doi:10.1007/978-1-4419-9967-2_1. ISBN 978-1-4419-9966-5. 
  18. ↑ "c-MYC Generates Repair Errors via Increased Transcription of Alternative-NHEJ Factors, LIG3 and PARP1, in Tyrosine Kinase-Activated Leukemias". Mol. Cancer Res. 13 (4): 699–712. 2015. doi:10.1158/1541-7786.MCR-14-0422. PMID 25828893. 
  19. ↑ "Alternative NHEJ Pathway Components Are Therapeutic Targets in High-Risk Neuroblastoma". Mol. Cancer Res. 13 (3): 470–482. 2015. doi:10.1158/1541-7786.MCR-14-0337. PMID 25563294. 
  20. ↑ "PARP expression in germ cell tumours". J. Clin. Pathol. 66 (7): 607–612. 2013. doi:10.1136/jclinpath-2012-201088. PMID 23486608. 
  21. ↑ "Poly(ADP-ribose) polymerase turnover alterations do not contribute to PARP overexpression in Ewing's sarcoma cells". Oncol. Rep. 9 (3): 529–532. 2002. doi:10.3892/or.9.3.529. PMID 11956622. 
  22. ↑ "Overexpression and hypomethylation of flap endonuclease 1 gene in breast and other cancers". Mol. Cancer Res. 6 (11): 1710–1717. 2008. doi:10.1158/1541-7786.MCR-08-0269. PMID 19010819. 
  23. ↑ "Flap endonuclease 1 is overexpressed in prostate cancer and is associated with a high Gleason score". BJU Int. 98 (2): 445–451. 2006. doi:10.1111/j.1464-410X.2006.06224.x. PMID 16879693. 
  24. ↑ "Identification of gastric cancer-related genes using a cDNA microarray containing novel expressed sequence tags expressed in gastric cancer cells". Clin. Cancer Res. 11 (2 Pt 1): 473–482. 2005. doi:10.1158/1078-0432.473.11.2. PMID 15701830. 
  25. ↑ "Flap endonuclease 1 is a promising candidate biomarker in gastric cancer and is involved in cell proliferation and apoptosis". Int. J. Mol. Med. 33 (5): 1268–1274. 2014. doi:10.3892/ijmm.2014.1682. PMID 24590400. 
  26. ↑ "Genome-wide analysis of gene expression in neuroblastomas detected by mass screening". Cancer Lett. 225 (1): 111–120. 2005. doi:10.1016/j.canlet.2004.10.035. PMID 15922863. https://hal.archives-ouvertes.fr/hal-00157917/file/Cancer_Letters_2004.pdf. 
  27. ↑ "Exploration of global gene expression patterns in pancreatic adenocarcinoma using cDNA microarrays". Am. J. Pathol. 162 (4): 1151–1162. 2003. doi:10.1016/S0002-9440(10)63911-9. PMID 12651607. 
  28. ↑ "FEN1 is overexpressed in testis, lung and brain tumors". Anticancer Res. 29 (7): 2453–2459. 2009. PMID 19596913. 
  29. ↑ "DNA damage responses: mechanisms and roles in human disease: 2007 G.H.A. Clowes Memorial Award Lecture". Mol. Cancer Res. 6 (4): 517–524. 2008. doi:10.1158/1541-7786.MCR-08-0020. PMID 18403632. 
  30. ↑ Bernstein, C; Prasad, AR; Nfonsam, V; Bernstein, H. (2013). "Chapter 16: DNA Damage, DNA Repair and Cancer". in Chen, Clark. New Research Directions in DNA Repair. Rijeka. p. 413. ISBN 978-953-51-1114-6. 
  31. ↑ "Double strand breaks can initiate gene silencing and SIRT1-dependent onset of DNA methylation in an exogenous promoter CpG island". PLOS Genetics 4 (8): e1000155. 2008. doi:10.1371/journal.pgen.1000155. PMID 18704159. 
  32. ↑ "DNA damage, homology-directed repair, and DNA methylation". PLOS Genetics 3 (7): e110. July 2007. doi:10.1371/journal.pgen.0030110. PMID 17616978. 



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