EpigenomicsVol. 7, No. 7 EditorialTargeting melanoma: unusual epigenetics reveals the dynamic rewiring of metastatic cellsMiguel Vizoso & Manel EstellerMiguel Vizoso Epigenetics & Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain & Manel Esteller*Author for correspondence: E-mail Address: mesteller@idibell.cat Epigenetics & Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain Department of Physiological Sciences II, School of Medicine, University of Barcelona, 08007 Barcelona, Catalonia, Spain Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Catalonia, SpainPublished Online:6 Nov 2015https://doi.org/10.2217/epi.15.67AboutSectionsView ArticleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit View articleKeywords: cryptic promoterDNA hypomethylationdrug sensitivitymelanoma biomarkerTBC1D16References1 Goll MG, Bestor TH. Eukaryotic cytosine methyltransferases. Annu. Rev. Biochem. 74, 481–514 (2005).Crossref, Medline, CAS, Google Scholar2 Robertson KD. DNA methylation, methyltransferases, and cancer. Oncogene 20, 3139–3155 (2001).Crossref, Medline, CAS, Google Scholar3 Fernandez AF, Assenov Y, Martin-Subero JI et al. A DNA methylation fingerprint of 1628 human samples. Genome Res. 22, 407–19 (2012).Crossref, Medline, CAS, Google Scholar4 Esteller M, Garcia-Foncillas J, Andion E et al. Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N. Engl. J. Med. 343, 1350–1354 (2000).Crossref, Medline, CAS, Google Scholar5 Esteller M, Silva JM, Dominguez G et al. Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. J. Natl Cancer Inst. 92, 564–569 (2000).Crossref, Medline, CAS, Google Scholar6 Esteller M. Epigenetics in cancer. N. Engl. J. Med. 358, 1148–59 (2008).Crossref, Medline, CAS, Google Scholar7 Esteller M. Aberrant DNA methylation as a cancer-inducing mechanism. Annu. Rev. Pharmacol. Toxicol. 45, 629–656 (2005).Crossref, Medline, CAS, Google Scholar8 Herman JG, Baylin SB. Gene silencing in cancer in association with promoter hypermethylation. N. Engl. J. Med. 349, 2042–2054 (2003).Crossref, Medline, CAS, Google Scholar9 Moutinho C, Martinez-Cardus A, Santos C et al. Epigenetic inactivation of the BRCA1 interactor SRBC and resistance to oxaliplatin in colorectal cancer. J. Natl Cancer Inst. 106, djt322 (2014).Crossref, Medline, Google Scholar10 Sandoval J, Mendez-Gonzalez J, Nadal E et al. A prognostic DNA methylation signature for stage I non-small-cell lung cancer. J. Clin. Oncol. 31, 4140–4147 (2013).Crossref, Medline, Google Scholar11 Rhee I, Jair KW, Yen RW et al. CpG methylation is maintained in human cancer cells lacking DNMT1. Nature 404, 1003–1007 (2000).Crossref, Medline, CAS, Google Scholar12 Rhee I, Bachman KE, Park BH et al. DNMT1 and DNMT3b cooperate to silence genes in human cancer cells. Nature 416, 552–556 (2002).Crossref, Medline, CAS, Google Scholar13 Jin B, Robertson KD. DNA methyltransferases, DNA damage repair, and cancer. Adv. Exp. Med. Biol. 754, 3–29 (2013).Crossref, Medline, CAS, Google Scholar14 Tahiliani M, Koh KP, Shen Y et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324, 930–935 (2009).Crossref, Medline, CAS, Google Scholar15 Williams K, Christensen J, Helin K. DNA methylation: TET proteins-guardians of CpG islands? EMBO Rep. 13, 28–35 (2012).Crossref, CAS, Google Scholar16 Vizoso M, Ferreira HJ, Lopez-Serra P et al. Epigenetic activation of a cryptic TBC1D16 transcript enhances melanoma progression by targeting EGFR. Nat. Med. 21(7), 741–750 (2015).Crossref, Medline, CAS, Google Scholar17 Akavia UD, Litvin O, Kim J et al. An integrated approach to uncover drivers of cancer. Cell 143, 1005–1017 (2010).Crossref, Medline, CAS, Google Scholar18 Goueli BS, Powell MB, Finger EC et al. TBC1D16 is a Rab4A GTPase activating protein that regulates receptor recycling and EGF receptor signaling. Proc. Natl Acad. Sci. USA 109, 15787–15792 (2012).Crossref, Medline, CAS, Google Scholar19 Wagle N, Emery C, Berger MF et al. Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling. J. Clin. Oncol. 29, 3085–3096 (2011).Crossref, Medline, CAS, Google Scholar20 Robert C, Karaszewska B, Schachter J et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N. Engl. J. Med. 372, 30–39 (2015).Crossref, Medline, CAS, Google Scholar21 Larkin J, Chiarion-Sileni V, Gonzalez R et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373(1), 23–34 (2015).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetailsCited ByTre2-Bub2-Cdc16 Family Proteins Based Nomogram Serve as a Promising Prognosis Predicting Model for Melanoma28 October 2020 | Frontiers in Oncology, Vol. 10Epigenetics of skin cancer: Interventions by selected bioactive phytochemicals3 November 2017 | Photodermatology, Photoimmunology & Photomedicine, Vol. 34, No. 1 Vol. 7, No. 7 Follow us on social media for the latest updates Metrics Downloaded 78 times History Published online 6 November 2015 Published in print October 2015 Information© Future Medicine LtdKeywordscryptic promoterDNA hypomethylationdrug sensitivitymelanoma biomarker TBC1D16 AcknowledgementsThe authors thank the patients and their families.Financial & competing interests disclosureThe research leading to these results has received funding from the European Community's Seventh Framework Programme FP7/2007–2013 under grant agreement no. PIAPP-GA-2009-230614-Target-Melanoma project (M Esteller), the Worldwide Cancer Research grant reference no. 15-0354 (M Esteller), the European Research Council Advanced grant no. 268626-EPINORC project (M Esteller), the Ministerio de Ciencia e Innovación grant numbers SAF2011-22803 (M Esteller), the Cellex Foundation (M Esteller) and 2014-SGR 633 (M Esteller). M Vizoso was supported by a Formación de Profesorado Universitario fellowship from the Spanish Ministry of Education. M Esteller is an Institucio Catalana de Recerca i Estudis Avançats Research Professor. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download
An important question in the field of cancer epigenetics involves the causes of CpG island hypermethylation in tumor suppressor genes leading to transcriptional silencing. L. Di Croce et al. recently shed some light on this subject (“Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor,” Reports, 8 Feb., p. [1079][1]). They report that the leukemia-promoting PML-RAR fusion protein may be an important cause of this epigenetic aberration. However, several lines of evidence suggest that this experimental model does not explain the accumulating data concerning promoter region methylation. In this experimental model, expression of the PML-RAR transcript with an exogenous construct leads to recruitment of DNMT1 and DNMT3a and increased methylation of a RARβ-Luc fusion construct or the endogenous promoter. Consistent with this, seven of nine primary acute promyelocytic leukemias (APLs) had methylation of the 5′ region of the endogenous RARβ βgene. Our own analysis suggests that the frequency of methylation of RARβ2 is the same in APLs that have the PML-RAR translocation as it is in other subtypes of acute myelogenous leukemia (AML) that do not have this alteration (see figure). This suggests that the presence of the PML-RAR translocation is neither necessary nor sufficient to induce RARβ2 methylation. In fact, many other malignancies have RARβ2 methylation without this translocation (see figure), in some cases more commonly than APL. We have also observed that APL patients with the PML-RAR translocations have the same frequency of CpG island hypermethylation of p15INK4b, CDH1, and p73 (all of them with potential RAR elements in their promoters) and global genomic methylation as other AML subtypes without the translocation (see figure). These observations prompt us to caution the extension of the experimental studies described into the more complex genetic and epigenetic alterations observed in primary human malignancies. # Response {#article-title-2} We recently demonstrated that, in APLS, PML-RAR promotes specific methylation of its target gene RARβ2 by recruiting DNA methyltransferases (DNMTs) to the promoter region. On the basis of these findings, we have proposed a general mechanism for the specificity of DNA methylation in cancer cells, e.g., aberrant recruitment of DNMTs by oncogenic transcription factors to specific regulative loci. Esteller et al . now report that the frequency of RARβ2 methylation (and other RA-target genes) is similar for APLs, which express PML-RAR, and other subtypes of AMLs, which do not express this fusion protein, and they question the importance of the role of PML-RAR in RARβ2 methylation. The mechanism(s) responsible for RARβ2 methylation in AMLs is presently unknown. On the basis of our proposed model, RARβ2 methylation in AMLs might be triggered by AML-specific fusion proteins. Indeed, one of the two components of each fusion protein is generally a transcription factor, so that AML-associated fusion proteins function as aberrant transcriptional regulators (similar to PML-RAR in APLs). We have recently shown that transcriptional repression of RA signaling is a common feature of AMLs. In particular, we have shown that AML1-ETO , the most common AML-associated fusion protein, is an HDAC-dependent repressor of RA signaling, thereby suggesting that RA target genes (such as RARβ2 and potentially the p15INK4b, CDH1, and p73 genes mentioned by Esteller et al .) are deregulated by AML-fusion proteins ([1][2]). Thus, the data reported by Esteller et al . do not contradict our model. Rather, they suggest that methylation of RA target genes is a frequent event in leukemias. Further investigation is required to decipher the mechanistic roles of AML-associated fusion proteins in establishing specific DNA methylation in AMLs. A similar scenario (aberrant recruitment of DNMTs by oncogenic transcription factors) can be envisioned for RARβ2 methylation in other cancers. Indeed, we are currently investigating the interactions between DNMTs and general transcription factors, both in normal and transformed cells. However, we cannot rule out the possibility that, in some tumors, RARβ2 methylation is caused by secondary mechanism(s). 1. [↵][3]1. F. F. Ferrara 2. et al. , Cancer Res. 61, 2 (2001). [OpenUrl][4][Abstract/FREE Full Text][5] [1]: /lookup/doi/10.1126/science.1065173 [2]: #ref-1 [3]: #xref-ref-1-1 View reference 1 in text [4]: {openurl}?query=rft.jtitle%253DCancer%2BResearch%26rft.stitle%253DCancer%2BRes.%26rft.issn%253D0008-5472%26rft.aulast%253DFerrara%26rft.auinit1%253DF.%2BF.%26rft.volume%253D61%26rft.issue%253D1%26rft.spage%253D2%26rft.epage%253D7%26rft.atitle%253DHistone%2BDeacetylase-targeted%2BTreatment%2BRestores%2BRetinoic%2BAcid%2BSignaling%2Band%2BDifferentiation%2Bin%2BAcute%2BMyeloid%2BLeukemia%26rft_id%253Dinfo%253Apmid%252F11196162%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [5]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NjoiY2FucmVzIjtzOjU6InJlc2lkIjtzOjY6IjYxLzEvMiI7czo0OiJhdG9tIjtzOjI1OiIvc2NpLzI5Ny81NTg4LzE4MDcuNC5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=
Metastasis is the sequence of interrelated steps by which primary tumor cells acquire the capability to invade adjacent tissue, enter the systemic circulation (intravasate), translocate through the vasculature, arrest in distant capillaries, extravasate into the surrounding tissue parenchyma, and, finally, proliferate from micrometastases into macroscopic secondary tumors [1, 2]. This metastatic process is the cause of 90 percent of deaths in patients with solid tumors [1, 2]. Therefore, unraveling the inner mechanisms of the pathogenesis of metastasis at systemic, cellular, and molecular levels has become a major goal of cancer research [1, 2].
Appears in: EDULEARN16 Proceedings Publication year: 2016Pages: 6268-6273ISBN: 978-84-608-8860-4ISSN: 2340-1117doi: 10.21125/edulearn.2016.0347Conference name: 8th International Conference on Education and New Learning TechnologiesDates: 4-6 July, 2016Location: Barcelona, Spain
Epigenetic processes, defined as the heritable patterns of gene expression that do not involve changes in the sequence of the genome, and their effects on gene repression are increasingly understood to be such a way of modulating phenotype transmission and development. The patterns of DNA methylation, histone modifications, microRNAs, and several chromatin-related proteins of sick cells usually differ from those of healthy cells, highlighting the importance of epigenetic regulation in most human pathologies. This chapter provides an overview of how epigenetic factors contribute to the development of human diseases, such as abnormal imprinting-causative pathologies, cancer malignancies, as well as autoimmune, cardiovascular, and neurological disorders. These studies have provided extensive information about the mechanisms that contribute to the phenotype of human diseases, but also provided opportunities for therapy.
Cancer is as much an epigenetic disease as it is a genetic and cytogenetic disease. The discovery that drastic changes in DNA methylation and histone modifications are commonly found in human tumors has inspired various laboratories and pharmaceutical companies to develop and study epigenetic drugs. One of the most promising groups of agents is the inhibitors of histone deacetylases (HDACs), which have different biochemical and biologic properties but have a single common activity: induction of acetylation in histones, the key proteins in nucleosome and chromatin structure. One of the main mechanisms of action of HDAC inhibitors is the transcriptional reactivation of dormant tumor-suppressor genes, such as p21WAF1. However, their pleiotropic nature leaves open the possibility that their well-known differentiation, cell-cycle arrest and apoptotic properties are also involved in other functions associated with HDAC inhibition. Many phase I clinical trials indicate that HDAC inhibitors appear to be well-tolerated drugs. Thus, the field is ready for rigorous biologic and clinical scrutiny to validate the therapeutic potential of these drugs. Our current data indicate that the use of HDAC inhibitors, probably in association with classical chemotherapy drugs or in combination with DNA-demethylating agents, could be promising for cancer patients.
