Epigenetic loss of the familial tumor-suppressor gene exostosin-1 (EXT1) disrupts heparan sulfate synthesis in cancer cells

Ropero, Santiago; Setién, Fernando; Espada, Jesús; Fraga, Mario F.; Herranz, Michel; Asp, Julia; Benassi, Maria Serena; Franchi, Alessandro; Patiño, Ana; Ward, Laura Sterian; Bovée, Judith; Cigudosa, Juan C.; Wim, Wuyts; Esteller, Manel

doi:10.1093/hmg/ddh298

Cited by 81 publications

(63 citation statements)

References 46 publications

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“…Additionally, we detected a submicroscopic 6.2-Mbp deletion on Chr8q that harbors only 4 genes: CSMD3, TRP51, EXT1, and SAMD12 (supplemental Figure 1A). Interestingly, EXT1 could be considered a putative driver gene, since it was found that EXT1 CpG island hypermethylation is common in leukemia, especially in acute promyelocytic leukemia and acute lymphoblastic leukemia, and nonmelanoma skin cancer 25 ( Figure 1). We also found a putative driver mutation in DLEC1 (p.D1772delD) which has already been reported for an AML case 26 and in kidney tumor (Catalog of Somatic Mutations in Cancer: COSM308378); moreover, epigenetic silencing of this gene was detected in the majority of Hodgkin and non-Hodgkin lymphomas.…”

Section: Resultsmentioning

confidence: 99%

Exome sequencing identifies putative drivers of progression of transient myeloproliferative disorder to AMKL in infants with Down syndrome

Nikolaev

Santoni

Vannier

et al. 2013

Blood

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Key Points• DS TMD shows no DNA rearrangements and a low rate of mutations other than GATA1.• DS AMKL always has rearrangements and mutations in genes known for leukemic progression; affected pathways share upregulation of MYC.Some neonates with Down syndrome (DS) are diagnosed with self-regressing transient myeloproliferative disorder (TMD), and 20% to 30% of those progress to acute megakaryoblastic leukemia (AMKL). We performed exome sequencing in 7 TMD/AMKL cases and copy-number analysis in these and 10 additional cases. All TMD/AMKL samples contained GATA1 mutations. No exome-sequenced TMD/AMKL sample had other recurrently mutated genes. However, 2 of 5 TMD cases, and all AMKL cases, showed mutations/deletions other than GATA1, in genes proven as transformation drivers in non-DS leukemia (EZH2, APC, FLT3, JAK1, PARK2-PACRG, EXT1, DLEC1, and SMC3). One patient at the TMD stage revealed 2 clonal expansions with different GATA1 mutations, of which 1 clone had an additional driver mutation. Interestingly, it was the other clone that gave rise to AMKL after accumulating mutations in 7 other genes. Data suggest that GATA1 mutations alone are sufficient for clonal expansions, and additional driver mutations at the TMD stage do not necessarily predict AMKL progression. Later in infancy, leukemic progression requires "third-hit driver" mutations/somatic copy-number alterations found in non-DS leukemias. Putative driver mutations affecting WNT (winglessrelated integration site), JAK-STAT (Janus kinase/signal transducer and activator of transcription), or MAPK/PI3K (mitogenactivated kinase/phosphatidylinositol-3 kinase) pathways were found in all cases, aberrant activation of which converges on overexpression of MYC. (Blood. 2013;122(4):554-561)

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Section: Resultsmentioning

confidence: 99%

Exome sequencing identifies putative drivers of progression of transient myeloproliferative disorder to AMKL in infants with Down syndrome

Nikolaev

Santoni

Vannier

et al. 2013

Blood

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“…The cell lines represented three different types of malignancies, colon (HCT-116 and COLO-205), breast (MCF-7 and MDA-MB-231), and leukemia (HL-60, U937, and REH). Cell lines were maintained in appropriate media and treated with 1 M 5-aza-2Ј-deoxycytidine (Sigma) for 3 days to achieve demethylation (19,21,22). WS Ϫ͞Ϫ cells (AG11395) were obtained from the Coriell Cell Repositories (Camden, NJ).…”

Section: Methodsmentioning

confidence: 99%

“…It is not only a matter of restoring gene expression but also of rescuing gene functionality. This is exemplified by several genes that undergo methylation-associated silencing, such as the DNA-repair gene hMLH1, the MDM2-regulator p14 ARF , or the glycosyltransferase EXT-1, where treatment with the demethylating agent induced recovery of gene functions: DNA mismatch repair activity, sequestration of MDM2, and heparan sulfate biosynthesis, respectively (19,21,22). Because WRN is the only RecQ member that exhibits exonuclease activity (9), we examined the impact of WRN methylation-mediated silencing in this enzymatic function of WRN and the effect of restoring WRN expression by pharmacological means.…”

Section: Wrn Promoter Cpg Island Hypermethylation Leads To Gene Inactmentioning

confidence: 99%

Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer

Agrelo

Cheng

Setién

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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240

227

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Werner syndrome (WS) is an inherited disorder characterized by premature onset of aging, genomic instability, and increased cancer incidence. The disease is caused by loss of function mutations of the WRN gene, a RecQ family member with both helicase and exonuclease activities. However, despite its putative tumorsuppressor function, little is known about the contribution of WRN to human sporadic malignancies. Here, we report that WRN function is abrogated in human cancer cells by transcriptional silencing associated with CpG island-promoter hypermethylation. We also show that, at the biochemical and cellular levels, the epigenetic inactivation of WRN leads to the loss of WRN-associated exonuclease activity and increased chromosomal instability and apoptosis induced by topoisomerase inhibitors. The described phenotype is reversed by the use of a DNA-demethylating agent or by the reintroduction of WRN into cancer cells displaying methylationdependent silencing of WRN. Furthermore, the restoration of WRN expression induces tumor-suppressor-like features, such as reduced colony formation density and inhibition of tumor growth in nude mouse xenograft models. Screening a large collection of human primary tumors (n ‫؍‬ 630) from different cell types revealed that WRN CpG island hypermethylation was a common event in epithelial and mesenchymal tumorigenesis. Most importantly, WRN hypermethylation in colorectal tumors was a predictor of good clinical response to the camptothecin analogue irinotecan, a topoisomerase inhibitor commonly used in the clinical setting for the treatment of this tumor type. These findings highlight the importance of WRN epigenetic inactivation in human cancer, leading to enhanced chromosomal instability and hypersensitivity to chemotherapeutic drugs. DNA methylationW erner syndrome (WS) is an autosomal recessive disease characterized by premature aging and a high incidence of malignant neoplasms (1, 2). Mutations in the WS gene (WRN) are found in patients exhibiting the clinical symptoms of WS (3-5). The vast majority of WRN mutations result in loss of function of the WRN protein (6). The WRN protein has been demonstrated to possess helicase and exonuclease activities (7-9), and cultures of WS cells show increased chromosomal instability, with abundant deletions, reciprocal translocations, and inversions (10, 11).WRN belong to the RecQ family of helicases, which are highly conserved from bacteria to human, and whose members are thought to be essential caretakers of the genome (11,12). In addition to WRN, germline mutations of two other RecQ helicases, BLM in Bloom syndrome and RECQL4 in Rothmund-Thomson syndrome, are also associated with an elevated incidence of cancer (12). Because patients with WRN germline mutations develop a broad spectrum of epithelial and mesenchymal tumors, which is one of the main causes of their death before the age of 50, a tumorsuppressor function for WRN has been proposed. This putative role is also supported by a very high rate of loss of heterozygosity at the chrom...

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“…The CpG island hypermethylation silenced tumour suppressor genes are genetically 'intact' and so reactivation by these DNA-demethylating agents completely restores their normal function, as has been demonstrated for the mismatch repair gene hMLH1, the MDM2-inhibitor p14 ARF , and the heparan sulphate enzyme exostosis-1 [22,32,39]. This release of gene silencing by the demethylating agent is not definitive and given sufficient time, that particular tumour suppressor gene will be completely shut down again by methylation.…”

Section: How Is the Chromatin Structure And Molecular Environment In mentioning

confidence: 99%

“…A striking example is to show that the re-introduction reduces colony formation [35][36][37]. It is also possible to test if the re-introduction of the gene inhibits xenograft growth in nude mice, as has been done for RASSF1A and EXT1 [38,39]. Finally, if mutations for that gene are not described, the generation of a knockout mouse may show a tumour-prone animal, as has been done for HIC-1 [40].…”

Section: How Do We Prove That Our Hypermethylated Gene Is Important Fmentioning

confidence: 99%

Dormant hypermethylated tumour suppressor genes: questions and answers

Esteller

2005

The Journal of Pathology

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The epigenetic inactivation of tumour suppressor genes by promoter CpG island methylation is nowadays one of the hottest topics in cancer research. However, there are still several important open questions: Can we use CpG island hypermethylation to classify tumours according to their clinical behaviour and chemosensitivity? How do we prove that our hypermethylated gene is important for cancer development and/or progression? Which enzymes are directly responsible for the CpG island hypermethylation of tumour suppressor genes? How is the chromatin structure and molecular environment in and around the hypermethylated CpG islands? Can we wake up these dormant hypermethylated tumour suppressor genes in an epigenetic therapy of cancer? Some answers are provided in this review, but other questions remain unsolved, awaiting the eager epigenetic researcher.

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Epigenetic loss of the familial tumor-suppressor gene exostosin-1 (EXT1) disrupts heparan sulfate synthesis in cancer cells

Cited by 81 publications

References 46 publications

Exome sequencing identifies putative drivers of progression of transient myeloproliferative disorder to AMKL in infants with Down syndrome

Exome sequencing identifies putative drivers of progression of transient myeloproliferative disorder to AMKL in infants with Down syndrome

Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer

Dormant hypermethylated tumour suppressor genes: questions and answers

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