Loss of imprinting of PEG1/MEST in lung cancer cell lines

Nakanishi, Hirofumi; Suda, Tetsuji; Katoh, Motonobu; Watanabe, Akiko; Igishi, Tadashi; Kodani, Masahiro; Matsumoto, Shingo; Nakamoto, Masaki; Shigeoka, Yasushi; Okabe, Tetsuro; Oshimura, Mitsuo; Shimizu, Eiji

doi:10.3892/or.12.6.1273

Cited by 35 publications

(34 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…ARMCX2 might have a role in tumour suppression based on the presence of an armadillo repeat motif, which is found in other proteins fulfilling functions in cell proliferation, migration, maintenance of tissue integrity and tumourigenesis, and has been involved in development (Smith et al, 2005). MEST, a maternally imprinted gene, has been implicated in embryonic growth and maternal behaviour (Lefebvre et al, 1998), and loss of MEST imprinting has been reported in breast and lung cancers (Pedersen et al, 2002;Nakanishi et al, 2004). Interestingly, it has recently been shown that MEST is a negative regulator of the Wnt pathway and that MEST knockdown might activate Wnt signalling (Jung et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Candidate DNA methylation drivers of acquired cisplatin resistance in ovarian cancer identified by methylome and expression profiling

et al. 2012

View full text Add to dashboard Cite

Multiple DNA methylation changes in the cancer methylome are associated with the acquisition of drug resistance; however it remains uncertain how many represent critical DNA methylation drivers of chemoresistance. Using isogenic, cisplatin-sensitive/resistant ovarian cancer cell lines and inducing resensitizaton with demethylating agents, we aimed to identify consistent methylation and expression changes associated with chemoresistance. Using genome-wide DNA methylation profiling across 27 578 CpG sites, we identified loci at 4092 genes becoming hypermethylated in chemoresistant A2780/cp70 compared with the parental-sensitive A2780 cell line. Hypermethylation at gene promoter regions is often associated with transcriptional silencing; however, expression of only 245 of these hypermethylated genes becomes downregulated in A2780/cp70 as measured by microarray expression profiling. Treatment of A2780/ cp70 with the demethylating agent 2-deoxy-5 0 -azacytidine induces resensitization to cisplatin and re-expression of 41 of the downregulated genes. A total of 13/41 genes were consistently hypermethylated in further independent cisplatin-resistant A2780 cell derivatives. CpG sites at 9 of the 13 genes (ARHGDIB, ARMCX2, COL1A, FLNA, FLNC, MEST, MLH1, NTS and PSMB9) acquired methylation in ovarian tumours at relapse following chemotherapy or chemoresistant cell lines derived at the time of patient relapse. Furthermore, 5/13 genes (ARMCX2, COL1A1, MDK, MEST and MLH1) acquired methylation in drug-resistant ovarian cancersustaining (side population) cells. MLH1 has a direct role in conferring cisplatin sensitivity when reintroduced into cells in vitro. This combined genomics approach has identified further potential key drivers of chemoresistance whose expression is silenced by DNA methylation that should be further evaluated as clinical biomarkers of drug resistance.

show abstract

Section: Discussionmentioning

confidence: 99%

Candidate DNA methylation drivers of acquired cisplatin resistance in ovarian cancer identified by methylome and expression profiling

et al. 2012

View full text Add to dashboard Cite

show abstract

“…These observations, along with the intrinsic monoallelic nature of imprinting, suggest that some imprinted genes may hold tumorigenic potential 5 . Indeed, loss-of-imprinting of several genes (for example, H19, IGF2 and MEST) has been correlated with different types of malignancies such as Wilm's tumour 6 , colorectal neoplasia 7 and lung cancer 8 . Nevertheless, the causative role of imprinting in tumorigenesis is still poorly understood, and the precise mechanisms by which imprinted genes may contribute to tumorigenicity remain to be elucidated.…”

mentioning

confidence: 99%

Involvement of parental imprinting in the antisense regulation of onco-miR-372-373

2013

View full text Add to dashboard Cite

The monoallelic nature of imprinted genes renders them highly susceptible to genetic and epigenetic perturbations, potentially resulting in transformation and disease. Here we show, using parthenogenetic induced pluripotent stem cells, an imprinted transcript that serves as an antisense regulator of onco-miR-372-3 (named anti-miR-371-3). As miR-372-3 have been shown to have an oncogenic role in testicular germ cell tumours, we study the involvement of their antisense transcript in these cells. Our results suggest that hypermethylation, leading to loss-of-expression of the imprinted antisense transcript, contributes to tumorigenic transformation by affecting the downstream target LATS2. Finally, we provide evidence for a tumour suppressive role of anti-miR-371-3, as its overexpression in tumour cells results in cell growth arrest and apoptosis, and prevents tumour formation on injection into immunodeficient mice.

show abstract

“…12 LOI of MEST in humans has been described in colorectal cancer 13 and lung-cancer cell lines. 14 LOI has also been reported in invasive breast cancer, 15 but the biallelic expression observed here is likely to be the result of a promoter usage switch between MEST isoforms. 16 Assisted reproductive technology (ART) and infertility may be associated with epigenetic defects.…”

Section: Introductionmentioning

confidence: 72%

“…48 Variable imprinting of MEST, including that of isoform 2, has also been reported between humanembryonic stem cell (hESCs) lines, raising concerns of the epigenetic stability of these cells. 40,49,50 In view of the observations of aberrant MEST methylation and imprinting with disease, 13,14,16 we considered it important to further characterise expression at the MEST locus in the embryos with expression arising from both alleles. Our data demonstrates that isoform 2 was the predominant MEST isoform detected in preimplantation embryos and show directly that imprinting of isoform 2 itself is variable between embryos (Figure 4d).…”

Section: Discussionmentioning

confidence: 99%

Variable imprinting of the MEST gene in human preimplantation embryos

et al. 2012

View full text Add to dashboard Cite

There is evidence that expression and methylation of the imprinted paternally expressed gene 1/mesoderm-specific transcript homologue (PEG1/MEST) gene may be affected by assisted reproductive technologies (ARTs) and infertility. In this study, we sought to assess the imprinting status of the MEST gene in a large cohort of in vitro-derived human preimplantation embryos, in order to characterise potentially adverse effects of ART and infertility on this locus in early human development. Embryonic genomic DNA from morula or blastocyst stage embryos was screened for a transcribed AflIII polymorphism in MEST and imprinting analysis was then performed in cDNA libraries derived from these embryos. In 10 heterozygous embryos, MEST expression was monoallelic in seven embryos, predominantly monoallelic in two embryos, and biallelic in one embryo. Screening of cDNA derived from 61 additional human preimplantation embryos, for which DNA for genotyping was unavailable, identified eight embryos with expression originating from both alleles (biallelic or predominantly monoallelic). In some embryos, therefore, the onset of imprinted MEST expression occurs during late preimplantation development. Variability in MEST imprinting was observed in both in vitro fertilization and intracytoplasmic sperm injection-derived embryos. Biallelic or predominantly monoallelic MEST expression was not associated with any one cause of infertility. Characterisation of the main MEST isoforms revealed that isoform 2 was detected in early development and was itself variably imprinted between embryos. To our knowledge, this report constitutes the largest expression study to date of genomic imprinting in human preimplantation embryos and reveals that for some imprinted genes, contrasting imprinting states exist between embryos.

show abstract

Loss of imprinting of PEG1/MEST in lung cancer cell lines

Cited by 35 publications

References 0 publications

Candidate DNA methylation drivers of acquired cisplatin resistance in ovarian cancer identified by methylome and expression profiling

Candidate DNA methylation drivers of acquired cisplatin resistance in ovarian cancer identified by methylome and expression profiling

Involvement of parental imprinting in the antisense regulation of onco-miR-372-373

Variable imprinting of the MEST gene in human preimplantation embryos

Contact Info

Product

Resources

About