The rs6983267 SNP Is Associated with MYC Transcription Efficiency, Which Promotes Progression and Worsens Prognosis of Colorectal Cancer

Takatsuno, Yasushi; Mimori, Koshi; Yamamoto, Ken; Sato, Tetsuya; Niida, Atsushi; Inoue, Hiroshi; Imoto, Seiya; Kawano, Shuichi; Yamaguchi, Rui; Toh, Hiroyuki; Iinuma, Hisae; Ishimaru, Shinya; Ishii, Hideshi; Suzuki, Sadao; Tokudome, Shinkan; Watanabe, Masahiko; Tanaka, Jun; Kudo, Shin Ei; Mochizuki, Hidetaka; Kusunoki, Masato; Yamada, Kazutaka; Shimada, Yasuhiro; Moriya, Yoshihiro; Miyano, Satoru; Sugihara, Kenichi; Mori, Masaki

doi:10.1245/s10434-012-2657-z

Cited by 45 publications

(37 citation statements)

References 24 publications

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“…In addition, in CRC patients with GG (but not TT) genotype, CCAT2 shows significant association with MYC expression levels, suggesting that the SNP status may also affect CCAT2 function as an RNA transcript. Although most of the previous studies failed to identify a correlation between this SNP and MYC expression, recent research found higher MYC expression in CRC samples containing GG alleles, probably due to the improved purity of the cancer tissues owing to the use of laser microdissection (Takatsuno et al 2012). Our findings on SNP-induced differential CCAT2 expression and function, together with the DNA enhancer element (Pomerantz et al 2009;Tuupanen et al 2009), provide an explanation on the cancer risk conferred by the rs6983267 risk allele (Fig.…”

Section: Discussionmentioning

confidence: 54%

CCAT2, a novel noncoding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer

et al. 2013

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The functional roles of SNPs within the 8q24 gene desert in the cancer phenotype are not yet well understood. Here, we report that CCAT2, a novel long noncoding RNA transcript (lncRNA) encompassing the rs6983267 SNP, is highly overexpressed in microsatellite-stable colorectal cancer and promotes tumor growth, metastasis, and chromosomal instability. We demonstrate that MYC, miR-17-5p, and miR-20a are up-regulated by CCAT2 through TCF7L2-mediated transcriptional regulation. We further identify the physical interaction between CCAT2 and TCF7L2 resulting in an enhancement of WNT signaling activity. We show that CCAT2 is itself a WNT downstream target, which suggests the existence of a feedback loop. Finally, we demonstrate that the SNP status affects CCAT2 expression and the risk allele G produces more CCAT2 transcript. Our results support a new mechanism of MYC and WNT regulation by the novel lncRNA CCAT2 in colorectal cancer pathogenesis, and provide an alternative explanation of the SNP-conferred cancer risk.[Supplemental material is available for this article.]Notwithstanding the considerable advancements in our understanding of the molecular genetic basis of cancer, in the majority of cancer-associated genomic regions, the responsible protein-coding genes have not been identified yet. The discovery of short (19-22 nt), noncoding RNAs (ncRNAs)-called microRNAs (miRNAs) (Ambros 2001)-not only revealed a novel mechanism of gene regulation but also led to the identification of miRNAs directly involved in cancer development (Spizzo et al. 2009). It is therefore plausible that as-yet-unidentified members of the broader category of ncRNA mapping to cancer-associated genomic regions play ratelimiting roles in tumor initiation and/or progression (Rinn and Chang 2012). For instance, we previously reported that highly conserved genomic regions (ultraconserved regions, or UCRs) (Bejerano et al. 2004) are frequently transcribed as long (>200 bp) ncRNAs (lncRNAs) in both normal and tumor tissues (Calin et al. 2007). Furthermore, germline mutations, as well as single nucleotide polymorphisms (SNPs) in ultraconserved ncRNAs, were found to occur more frequently in patients with colon cancer and chronic leukemia than in the general population (Wojcik et al. 2010).The rs6983267 SNP, mapping to the 8q24.21 chromosomal region, has been consistently associated with an increased risk of colorectal cancer (CRC) (Haiman et al. 2007): The G allele was associated with greater predisposition to CRC than the T allele (odds ratios of 1.27 and 1.47 for heterozygotes and homozygotes, respectively; P = 1.27 3 10 À14 ) (Tomlinson et al. 2007). The increased cancer risk from this SNP variant was also observed in other cancer types, including prostate, ovarian, and inflammatory breast cancer (Ghoussaini et al. 2008;Bertucci et al. 2012). Despite the consistent association between rs6983267 and cancer risk, the underlying molecular and cellular mechanisms remain largely unknown. The genomic region spanning rs6983267 was found to contain DNA (Pom...

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Section: Discussionmentioning

confidence: 54%

CCAT2, a novel noncoding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer

et al. 2013

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“…3f). Some reports have suggested that BubR1 is directly activated by MYC thorough inhibiting the anaphase-promoting complex [9,30]. Together, these results indicate that BubR1 is an important factor in CRC cases carrying the heterozygous GT allele of rs6983267 to promote cancer progression thorough MYC activation.…”

Section: Discussionmentioning

confidence: 55%

“…The GG allele has previously been associated with an increased risk of CRC [8]. Some studies have suggested that CRC patients with rs6983267 GG alleles demonstrate increased vascular invasion and poor survival through the upregulation of MYC transcription factor expression [9,10]. …”

Section: Introductionmentioning

confidence: 99%

The Expression of <b><i>CCAT2</i></b>, a Novel Long Noncoding RNA Transcript, and rs6983267 Single-Nucleotide Polymorphism Genotypes in Colorectal Cancers

Kasagi

Oki²,

Ando

et al. 2016

Oncology

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Colon cancer-associated transcription 2 (CCAT2) was recently identified as a novel long noncoding RNA transcript encompassing the single-nucleotide polymorphism rs6983267. CCAT2 is overexpressed in colorectal cancer (CRC) where it promotes tumor growth, metastasis, and chromosomal instability, although the clinical relevance of this enhanced expression is unknown. In this retrospective study, CCAT2 expression was evaluated using real-time polymerase chain reaction in 149 CRC patients, and its associations with clinicopathological characteristics, outcome, rs6983267 genotypes, microsatellite status, DNA ploidy, and BubR1 expression were analyzed. CCAT2 expression in cancer tissue was significantly higher than in noncancer tissue (p < 0.001), particularly in cases of metastatic cancer (p < 0.001). However, relative CCAT2 expression levels and rs6983267 genotypes were not correlated with clinicopathological features or patient prognosis. CRC cases demonstrating high CCAT2 expression were all microsatellite stable (p < 0.005). Together, this indicates that CCAT2 expression was associated with microsatellite-stable CRC.

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“…Each selected gene was divided into low and high expression groups at the median point of expression. Additionally, to verify the relevance of our results with GSE17536 database, we used another reference dataset for CRC patients (16). The 91 patients with both CRC stage and DFS time information were selected from this reference dataset and used in validation analysis.…”

Section: Methodsmentioning

confidence: 99%

“…We performed the same prognosis analysis for cancer recurrence with another reference dataset (16) to confirm that this biological behavior is not unique to the GSE17536 database. Also the validation results showed the same tendency that the patients with imbalanced expression of IDH1/2 had a shorter DFS compared to those with balanced expression (Fig.…”

Section: Imbalance Between the Idh1 And Idh2 Expression Is Associatedmentioning

confidence: 99%

Mathematical analysis predicts imbalanced IDH1/2 expression associates with 2-HG-inactivating β-oxygenation pathway in colorectal cancer

Koseki

Colvin

Fukusumi

et al. 2015

International Journal of Oncology

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Bioinformatics and computational modeling offer innovative approaches to investigate cancer metabolism and predict the secondary and tertiary cellular responses. Dysregulation of metabolism has also been implicated in the pathophysiology of cancer. A significant proportion of patients with glioblastoma and hematological malignancies harbor the mutated forms of the oxidative phosphorylation (OxPhos) enzymes, isocitrate dehydrogenase (IDH) 1 or 2. The mutated forms of IDH1 and IDH2 produce an oncogenic metabolite, D-2-hydroxyglutarate (D2HG). A recent study of breast cancer patients showed that D2HG can also be produced in the absence of mutated IDH, through an alternative route involving over-activated MYC signaling. We developed a novel methodology to computationally analyze gene expression in colorectal cancer (CRC), and identified novel sets of genes that are associated with patient survival. The study of OxPhos-related genes revealed that an imbalance between the expression of IDH1 and IDH2, defined as overexpression of one isoform in relation to the other, was associated with worse prognosis in CRC patients. This effect was further accentuated by reduced expression of the β-oxygenation enzyme, 3-D-hydroxyacyl-CoA dehydratase (HCDH) 4, which has been reported to contribute to metabolism of intracellular D2HG. The present computational analysis revealed a novel and potential mechanism of CRC development, through over-production of D2HG when there is an imbalance between IDH1 and IDH2 expression, resulting in decreased clearance of D2HG when the β-oxidization pathway is diminished. Additional validation analysis with another gene expression dataset resulted in IDH1/2 imbalanced expression with a shorter DFS compared with balanced expression. Altogether, these findings provide a strong rationale for studying this mechanism further in order to discover novel therapeutic targets for the treatment of CRC.

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The rs6983267 SNP Is Associated with MYC Transcription Efficiency, Which Promotes Progression and Worsens Prognosis of Colorectal Cancer

Abstract: The presence of the minor allele of rs6983267 at 8q24.21 worsened the prognosis of CRC through up-regulation of MYC transcription. Furthermore, progression of CRC may require global CNA in the presence of the major allele and with lack of MYC transcription.

Cited by 45 publications

References 24 publications

CCAT2, a novel noncoding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer

CCAT2, a novel noncoding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer

The Expression of <b><i>CCAT2</i></b>, a Novel Long Noncoding RNA Transcript, and rs6983267 Single-Nucleotide Polymorphism Genotypes in Colorectal Cancers

Mathematical analysis predicts imbalanced IDH1/2 expression associates with 2-HG-inactivating β-oxygenation pathway in colorectal cancer

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