Clinical significance of the interaction between non-coding RNAs and the epigenetics machinery

Figures & data

Figure 1. Non-coding RNAs, epigenetics and their diverse levels of regulation. (A) The gray box illustrates the classical Biology “Central Dogma” and the emergence of a new class of RNAs, the ncRNAs, and their main functions (B). The non-coding RNome is shown in the blue box, comprised by short and long ncRNAs and the epigenome is shown as a red box. Their levels of regulation are shown by arrows. The complexity of the interactions between the miRNome and the epigenome can be easily visualized.

Table 1. Summary of the most relevant findings in regard to epigenetics and non-coding RNAs

Type of lncRNA	Molecule	Cancer Type	Clinical significance	References
Epigenetic regulation of non-coding RNAs
microRNAs	miR-129–2	Hepatocellular carcinoma	miR-129–2 methylation was specifically detected in plasma samples. Potential marker for early diagnosis.	15
	miR-129–2	Hematological malignancies	miR-129–2 methylation was found as adversely impacting survival in chronic lymphocytic leukemia (CLL)	16
	miR-124–3	Renal carcinoma	Increased methylation of miR-124–3 CpG islands associated with unfavorable prognosis such as tumor grade and diameter, metastasis and advanced disease.	18
	miR-124	Acute lymphoblastic leukemia	Hypermethylation of this locus was found as an independent prognostic factor for overall and disease-free survival and associated with higher relapse and mortality rates.	19
	miR-34a	Colon cancer	Methylation of miR-34 associated with metastasis to liver and lymph nodes	20
	miR-212	Lung cancer	Silencing of miR-212 was correlated with later stages of the disease – staging T3/T4	22
lncRNAs	H19	Hepatocellular carcinoma	H19 involved disease progression	25
	H19	Hepatocellular carcinoma	Epigenetic activation of miR-200 family promotes H19 downregulation, driving metastasis through EMT induction. Low T/R ratio was associated with poor prognosis.	26
	KIAA0495, PART1, MGC21881, MIAT, GAS5 and PAR5	Glioblastoma multiforme	The six-lncRNA signature was linked with overall survival, alluding that this signature may possibly supply new markers for prognosis treatment and outcome prediction.	27
	ANRIL	Cancer in general	Epigenetic modifications contribute to its silencing, which may bring both diagnostic and prognostic perspectives in the future.	30
Non-coding RNAs as regulators of epigenetics
epi-miRs	miR-29 family	Lung cancer	Lower survival rates in patients with high levels of DNMT3A	31
	miR-22	Hepatocellular carcinoma	Decreased survival and worse prognosis when miR-22 was downregulated.	32
piRNAs	Hiwi	Esophageal squamous cell carcinoma	Hiwi (Piwi human ortholog) associated with poor prognosis	46
lncRNAs	XIST	Testicular germ cells tumor	Methylation status as a biomarker in plasma for early detection and prognosis.	43
	HOTAIR	Laryngeal squamous cell carcinoma	Associated with poor tumor differentiation, lymph node metastasis and advanced clinical stages	44
	HOTAIR	Breast cancer (primary and metastasis)	Predictor of metastasis and survival	45

Calin GA, Croce CM. MicroRNA signatures in human cancers. Nat Rev Cancer 2006; 6:857 - 66; http://dx.doi.org/10.1038/nrc1997; PMID: 17060945

 PubMed Web of Science ®Google Scholar

Calin GA, Ferracin M, Cimmino A, Di Leva G, Shimizu M, Wojcik SE, Iorio MV, Visone R, Sever NI, Fabbri M, et al. A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. N Engl J Med 2005; 353:1793 - 801; http://dx.doi.org/10.1056/NEJMoa050995; PMID: 16251535

 PubMed Web of Science ®Google Scholar

Lu CY, Lin KY, Tien MT, Wu CT, Uen YH, Tseng TL. Frequent DNA methylation of MiR-129-2 and its potential clinical implication in hepatocellular carcinoma. Genes Chromosomes Cancer 2013; 52:636 - 43; PMID: 23580407

 PubMed Web of Science ®Google Scholar

Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100:57 - 70; http://dx.doi.org/10.1016/S0092-8674(00)81683-9; PMID: 10647931

 PubMed Web of Science ®Google Scholar

Wong KY, Yim RL, Kwong YL, Leung CY, Hui PK, Cheung F, Liang R, Jin DY, Chim CS. Epigenetic inactivation of the MIR129-2 in hematological malignancies. J Hematol Oncol 2013; 6:16; http://dx.doi.org/10.1186/1756-8722-6-16; PMID: 23406679

 PubMed Web of Science ®Google Scholar

Gebauer K, Peters I, Dubrowinskaja N, Hennenlotter J, Abbas M, Scherer R, Tezval H, Merseburger AS, Stenzl A, Kuczyk MA, et al. Hsa-mir-124-3 CpG island methylation is associated with advanced tumours and disease recurrence of patients with clear cell renal cell carcinoma. Br J Cancer 2013; 108:131 - 8; http://dx.doi.org/10.1038/bjc.2012.537; PMID: 23321515

 PubMed Web of Science ®Google Scholar

Lujambio A, Calin GA, Villanueva A, Ropero S, Sánchez-Céspedes M, Blanco D, Montuenga LM, Rossi S, Nicoloso MS, Faller WJ, et al. A microRNA DNA methylation signature for human cancer metastasis. Proc Natl Acad Sci U S A 2008; 105:13556 - 61; http://dx.doi.org/10.1073/pnas.0803055105; PMID: 18768788

 PubMed Web of Science ®Google Scholar

Incoronato M, Urso L, Portela A, Laukkanen MO, Soini Y, Quintavalle C, Keller S, Esteller M, Condorelli G. Epigenetic regulation of miR-212 expression in lung cancer. PLoS One 2011; 6:e27722; http://dx.doi.org/10.1371/journal.pone.0027722; PMID: 22110741

 PubMedGoogle Scholar

Djebali S, Davis CA, Merkel A, Dobin A, Lassmann T, Mortazavi A, Tanzer A, Lagarde J, Lin W, Schlesinger F, et al. Landscape of transcription in human cells. Nature 2012; 489:101 - 8; http://dx.doi.org/10.1038/nature11233; PMID: 22955620

 PubMed Web of Science ®Google Scholar

Zhang L, Yang F, Yuan JH, Yuan SX, Zhou WP, Huo XS, Xu D, Bi HS, Wang F, Sun SH. Epigenetic activation of the MiR-200 family contributes to H19-mediated metastasis suppression in hepatocellular carcinoma. Carcinogenesis 2013; 34:577 - 86; http://dx.doi.org/10.1093/carcin/bgs381; PMID: 23222811

 PubMed Web of Science ®Google Scholar

Zhang XQSS, Sun S, Lam KF, Kiang KM, Pu JK, Ho AS, Lui WM, Fung CF, Wong TS, Leung GK. A long non-coding RNA signature in glioblastoma multiforme predicts survival. Neurobiol Dis 2013; 58:123 - 31; http://dx.doi.org/10.1016/j.nbd.2013.05.011; PMID: 23726844

 PubMed Web of Science ®Google Scholar

Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S, Donovan J, Barretina J, Boehm JS, Dobson J, Urashima M, et al. The landscape of somatic copy-number alteration across human cancers. Nature 2010; 463:899 - 905; http://dx.doi.org/10.1038/nature08822; PMID: 20164920

 PubMed Web of Science ®Google Scholar

Brown CJ, Hendrich BD, Rupert JL, Lafrenière RG, Xing Y, Lawrence J, Willard HF. The human XIST gene: analysis of a 17 kb inactive X-specific RNA that contains conserved repeats and is highly localized within the nucleus. Cell 1992; 71:527 - 42; http://dx.doi.org/10.1016/0092-8674(92)90520-M; PMID: 1423611

 PubMed Web of Science ®Google Scholar

Braconi C, Huang N, Patel T. MicroRNA-dependent regulation of DNA methyltransferase-1 and tumor suppressor gene expression by interleukin-6 in human malignant cholangiocytes. Hepatology 2010; 51:881 - 90; PMID: 20146264

 PubMed Web of Science ®Google Scholar

Stumpel DJ, Schotte D, Lange-Turenhout EA, Schneider P, Seslija L, de Menezes RX, Marquez VE, Pieters R, den Boer ML, Stam RW. Hypermethylation of specific microRNA genes in MLL-rearranged infant acute lymphoblastic leukemia: major matters at a micro scale. Leukemia 2011; 25:429 - 39; http://dx.doi.org/10.1038/leu.2010.282; PMID: 21116279

 PubMed Web of Science ®Google Scholar

Duursma AM, Kedde M, Schrier M, le Sage C, Agami R. miR-148 targets human DNMT3b protein coding region. RNA 2008; 14:872 - 7; http://dx.doi.org/10.1261/rna.972008; PMID: 18367714

 PubMed Web of Science ®Google Scholar