Gene Summary

Gene:KCNQ1OT1; KCNQ1 opposite strand/antisense transcript 1
Aliases: LIT1, Kncq1, KvDMR1, KCNQ10T1, KCNQ1-AS2, KvLQT1-AS, NCRNA00012
Summary:Human chromosomal region 11p15.5 contains two clusters of epigenetically-regulated genes that are expressed from only one chromosome in a parent-of-origin manner. Each cluster, or imprinted domain, is regulated by a functionally independent imprinting control region (ICR). The human CDKN1C/KCNQ1OT1 domain is regulated by an ICR located in an intron of KCNQ1, and contains at least eight genes that are expressed exclusively or preferentially from the maternally-inherited allele. The DNA of the ICR is specifically methylated on the maternally-inherited chromosome, and unmethylated on the paternally-inherited chromosome. The ICR contains the promoter of the KCNQ1OT1 gene that is exclusively expressed from the paternal allele. The KCNQ1OT1 transcript is the antisense to the KCNQ1 gene and is a unspliced long non-coding RNA. It interacts with chromatin and regulates transcription of multiple target genes through epigenetic modifications. The transcript is abnormally expressed from both chromosomes in most patients with Beckwith-Wiedemann syndrome, and the transcript also plays an important role in colorectal carcinogenesis. [provided by RefSeq, Apr 2012]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 31 August, 2019

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Graph generated 31 August 2019 using data from PubMed using criteria.

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Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Latest Publications: KCNQ1OT1 (cancer-related)

Bruno C, Blagoskonov O, Barberet J, et al.
Sperm imprinting integrity in seminoma patients?
Clin Epigenetics. 2018; 10(1):125 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Testicular germ cell tumor such as seminoma is strongly associated with male reproductive problems commonly associated with the alteration of sperm parameters as described in testicular dysgenesis syndrome. Interestingly, numerous studies have reported that the precursor of germ cell cancer, germ cell neoplasia in situ (GCNIS), present similarities to fetal gonocytes, specifically characterized by global DNA hypomethylation particularly on imprinting sequences. These disorders may have a common origin derived from perturbations of embryonal programming during fetal development. Presently, there is no available information concerning the sperm DNA methylation patterns of testicular cancer patients. For the first time, we evaluated the sperm imprinting of seminoma patients. A total of 92 cryopreserved sperm samples were included, 31 before seminoma treatment (S): 23 normozoospermic (SN) and 8 oligozoospermic (SO) and 61 sperm controls samples: 31 normozoospermic (N) and 30 oligozoospermic (O). DNA methylation levels of seven differentially methylated regions (DMRs) of imprinted genes [H19/IGF2: IG-DMR (CTCF3 and CTCF6 of H19 gene); IGF2-DMRs (DMR0 and DMR2); MEG3/DLK1:IG-DMR; SNURF:TSS-DMR; KCNQ1OT1:TSS-DMR] were assessed by pyrosequencing. All comparative analyses were adjusted for age.
RESULTS: Comparisons of sperm DNA methylation levels between seminoma (S) and normozoospermic (N) samples showed a significant difference for the SNURF sequence (p = 0.017), but after taking into account the sperm parameters, no difference was observed. However, we confirmed a significant association between oligozoospermia (O) and imprinting defects for H19/IGF2-CTCF6 (p = 0.001), MEG3/DLK1 (p = 0.017), IGF2-DMR2 (p = 0.022), and SNURF (p = 0.032) in comparison with control groups (N).
CONCLUSIONS: This study highlights the high risk of sperm imprinting defects in cases of oligozoospermia and shows for the first time that seminoma patients with normal spermatogenesis present sperm imprinting integrity. These data suggest a low probability of the involvement of a common imprinting defect in fetal cells leading to both TGCT and subfertility.

Sun H, Li Y, Kong H, et al.
Dysregulation of KCNQ1OT1 promotes cholangiocarcinoma progression via miR-140-5p/SOX4 axis.
Arch Biochem Biophys. 2018; 658:7-15 [PubMed] Related Publications
It is commonly recognized that aberrant expression of long non-coding RNAs (lncRNAs) is an important cause of cancer progression. The oncogenic property of KCNQ1OT1 has been identified in several malignant tumors. Here, we decided to explore the biological function and molecular mechanism of KCNQ1OT1 in cholangiocarcinoma (CCA). The expression conditions of KCNQ1OT1 in different tissues and cell lines were examined with qRT-PCR analysis. As expected, KCNQ1OT1 was highly expressed in CCA tissues and cell lines. Results of functional assays revealed the oncogenic function of KCNQ1OT in cholangiocarcinoma progression. The positive effect of KCNQ1OT1 on cell proliferation, invasion and epithelial-mesenchymal transition was identified by performing MTT assay, colony formation assay, transwell invasion assay and western blotting. Whereas, the negative effect of KCNQ1OT1 on the cell apoptosis was tested with flow cytometry analysis. Mechanism investigation revealed that KCNQ1OT1 can act as a ceRNA to improve CCA progression by regulating miR-140-5p/SOX4 axis. Recue assays were conducted to demonstrate the actual effects of KCNQ1OT1-miR-140-5p-SOX4 pathway on CCA progression.

Zhang Z, Qian W, Wang S, et al.
Analysis of lncRNA-Associated ceRNA Network Reveals Potential lncRNA Biomarkers in Human Colon Adenocarcinoma.
Cell Physiol Biochem. 2018; 49(5):1778-1791 [PubMed] Related Publications
BACKGROUND/AIMS: Long non-coding RNAs (lncRNAs) acting as competing endogenous RNAs (ceRNAs) play significant roles in the development of tumors, but the functions of specific lncRNAs and lncRNA-related ceRNA networks have not been fully elucidated for colon adenocarcinoma (COAD). In this study, we aimed to clarify the lncRNA-microRNA (miRNA)-mRNA ceRNA network and potential lncRNA biomarkers in COAD.
METHODS: We extracted data from The Cancer Genome Atlas (TCGA) and identified COAD-specific mRNAs, miRNAs, and lncRNAs. The biological processes in Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were analyzed for COAD-specific mRNAs. We then constructed a ceRNA network of COAD-specific mRNAs, miRNAs and lncRNAs and analyzed the correlation between expression patterns and clinical features of the lncRNAs involved. After identifying potential mRNA targets of 4 lncRNAs related to overall survival (OS), we conducted stepwise analysis of these targets through GO and KEGG. Using tissue samples from our own patients, we also verified certain analytical results using quantitative real-time PCR (qRT-PCR).
RESULTS: Data from 521 samples (480 tumor tissue and 41 adjacent non-tumor tissue samples) were extracted from TCGA. A total of 258 specific lncRNAs, 206 specific miRNAs, and 1467 specific mRNAs were identified (absolute log2 [fold change] > 2, false discovery rate < 0.01). Analysis of KEGG revealed that specific mRNAs were enriched in cancer-related pathways. The ceRNA network was constructed with 64 lncRNAs, 18 miRNAs, and 42 mRNAs. Among these lncRNAs involved in the network, 3 lncRNAs (LINC00355, HULC, and IGF2-AS) were confirmed to be associated with certain clinical features and 4 lncRNAs (HOTAIR, LINC00355, KCNQ1OT1, and TSSC1-IT1) were found to be negatively linked to OS (log-rank p < 0.05). KEGG showed that the potential mRNA targets of these 4 lncRNAs may be concentrated in the MAPK pathway. Certain results were validated by qRT-PCR.
CONCLUSION: This study providing novel insights into the lncRNA-miRNA-mRNA ceRNA network and reveals potential lncRNA biomarkers in COAD.

Feng W, Wang C, Liang C, et al.
The Dysregulated Expression of KCNQ1OT1 and Its Interaction with Downstream Factors miR-145/CCNE2 in Breast Cancer Cells.
Cell Physiol Biochem. 2018; 49(2):432-446 [PubMed] Related Publications
BACKGROUND/AIMS: Next-generation sequencing (NGS) has revealed abundant long noncoding RNAs (lncRNAs) that have been characterized as critical components of cancer biology in humans. The present study aims to investigate the role of the lncRNA KCNQ1OT1 in breast cancer (BRCA) as well as the underlying molecular mechanisms and functions of KCNQ1OT1 involved in the progression of BRCA.
METHODS: The Cancer Genome Atlas (TCGA) and StarBase v2.0 were used to obtain the required gene data. Dual luciferase reporter gene assays were conducted to verify the relevant intermolecular target relationships. QRT-PCR and Western blot were performed to measure the expression levels of different molecules. Cell proliferation was detected by using the MTT and colony formation assays, while cell migration and invasion were examined by transwell assay. Variations in cell apoptosis and cell cycle were determined through flow cytometry. A tumor xenograft model was applied to assess tumor growth in vivo.
RESULTS: KCNQ1OT1 was found to be remarkably highly expressed in BRCA tissues and cells. KCNQ1OT1 modulated CCNE2 through sponging miR-145 in BRCA. KCNQ1OT1 promoted tumor growth in vivo by regulating miR-145/CCNE2.
CONCLUSION: The KCNQ1OT1/miR-145/CCNE2 axis plays a critical regulatory role in BRCA, potentially giving rise to BRCA tumorigenesis and progression. These findings provide valuable evidence for improving the diagnosis and treatment of BRCA in the future.

Hu H, Yang L, Li L, Zeng C
Long non-coding RNA KCNQ1OT1 modulates oxaliplatin resistance in hepatocellular carcinoma through miR-7-5p/ ABCC1 axis.
Biochem Biophys Res Commun. 2018; 503(4):2400-2406 [PubMed] Related Publications
The underlying functions of long non-coding RNAs (lncRNAs) on chemoresistance in multiple cancers have been testified. However, the function and mechanism of lncRNAs on chemoresistance in hepatocellular carcinoma are still confused. In this study, we concentrated on the function and mechanism of KCNQ1OT1 on oxaliplatin resistance in hepatocellular carcinoma. Results showed that KCNQ1OT1 was significantly up-regulated in oxaliplatin-resistant HepG2 and Huh7 cells. Moreover, knockdown of KCNQ1OT1 inhibited the cell proliferation, migration, invasion and reduced the expression of drug-resistant gene (MRP5, MDR1, LRP1). Additionally, bioinformatics analysis and dual-luciferase reporter assay showed that miR-7-5p directly targeted the 3'-UTR of miR-7-5p and ABCC1 mRNA, indicating that KCNQ1OT1 regulated the expression of ABCC1 via endogenous sponging miR-7-5p. Conclusively, KCNQ1OT1 modulated oxaliplatin resistance in hepatocellular carcinoma through miR-7-5p/ABCC1 axis, indicating a novel approach for the treatment of hepatocellular carcinoma.

Guo B, Zhang Q, Wang H, et al.
KCNQ1OT1 promotes melanoma growth and metastasis.
Aging (Albany NY). 2018; 10(4):632-644 [PubMed] Free Access to Full Article Related Publications
Melanoma is the deadliest cutaneous neoplasm. To prevent metastasis, early diagnosis and surgical treatment is vital. Long non-coding RNAs (lncRNAs) may serve as biomarkers and therapeutic targets in tumors. We investigated the molecular mechanisms of lncRNA KCNQ1OT1 in melanoma. Real time PCR demonstrated that KCNQ1OT1 expression is up-regulated in melanoma tissues and cells. KCNQ1OT1 promoted cell proliferation and metastasis in melanoma. By directly bindin to miR-153, KCNQ1OT1 acted as a competing endogenous RNA (ceRNA) to de-repress MET expression. Our results may provide the basis for a novel strategy for early detection and/or treatment of melanoma.

Sun X, Xin Y, Wang M, et al.
Overexpression of long non-coding RNA KCNQ1OT1 is related to good prognosis via inhibiting cell proliferation in non-small cell lung cancer.
Thorac Cancer. 2018; 9(5):523-531 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Lung cancer (LC) is the most common malignancy in the world. Many long non-coding RNAs (lncRNAs) have been reported to be associated with LC; however, the function of KCNQ1OT1 in LC requires exploration.
METHODS: We conducted in silico analysis with data from The Cancer Genome Atlas to investigate the association between KCNQ1OT1 and LC. A Kaplan-Meier plotter was used to analyze the function of KCNQ1OT1 on LC patient prognosis. Quantitative reverse transcription-PCR (qRT-PCR) was performed to confirm previous results. An A549 lung cancer cell was transfected with pcDNA-KCNQ1OT1, and methyl thiazolyl tetrazolium assay was performed to investigate the function of KCNQ1OT1 on cell proliferation. in vivo assay was performed with nude mice.
RESULTS: Bioinformatics analysis and qRT-PCR indicated that KCNQ1OT1 expression was higher in stage I LC patients (P < 0.01), and survival analysis showed that high expression of KCNQ1OT1 in LC patients was associated with better prognosis (P < 0.05). qRT-PCR showed a negative correlation between KCNQ1OT1 and Ki67 expression and tumor size (P < 0.01), which indicated that KCNQ1OT1 is associated with tumor growth in LC. There was no significant correlation between KCNQ1OT1 level and lymph node metastasis (P > 0.05). KCNQ1OT1 overexpression significantly inhibited cell proliferation and tumor growth in vitro and in vivo (P < 0.05).
CONCLUSION: Our preliminary data showed that KCNQ1OT1 is overexpressed in early stage LC and is correlated with better prognosis in LC patients, possibly by suppressing cell proliferation.

Lu Q, Yu T, Ou X, et al.
Potential lncRNA diagnostic biomarkers for early gastric cancer.
Mol Med Rep. 2017; 16(6):9545-9552 [PubMed] Related Publications
Long noncoding RNAs (lncRNAs) serve important functions in many crucial biological processes; however, the effects of lncRNAs in early gastric cancer (EGC) are not entirely clear. The present study aimed to demonstrate the potential of lncRNAs to be used as biomarkers in EGC. Reverse transcription‑quantitative polymerase chain reaction was used to measure the expression levels of lncRNAs, including X inactive‑specific transcript (XIST), Yiya, brain cytoplasmic RNA 1 (BCYRN1), ribosomal RNA processing 1B (RRP1B), KCNQ1 opposite transcript 1 (KCNQ1OT1) and testes development related 1 (TDRG1), in EGC tissues compared with normal adjacent tissues (NATs). XIST, BCYRN1, RRP1B and TDRG1 were identified as differentially expressed in EGC tissues compared with NATs. The specificity and sensitivity of XIST, BCYRN1, RRP1B and TDRG1 were determined by receiver operating characteristic curve analysis. In addition, RRP1B expression was revealed to be significantly correlated with distal metastasis (P=0.020) and tumor‑node‑metastasis staging (P=0.018), and TDRG1 expression was significantly correlated with lymph node metastasis (P=0.001). Furthermore, BCYRN1, RRP1B and TDRG1 expression levels were compared between EGC tissues and plasma, and the results indicated that there were significant positive correlations of XIST, BCYRN1, RRP1B and TDRG1 expression levels between the EGC tissues and plasma. Therefore, the present study suggested that XIST, BCYRN1, RRP1B and TDRG1 may be served as potential diagnostic biomarkers for EGC.

Ren K, Xu R, Huang J, et al.
Knockdown of long non-coding RNA KCNQ1OT1 depressed chemoresistance to paclitaxel in lung adenocarcinoma.
Cancer Chemother Pharmacol. 2017; 80(2):243-250 [PubMed] Related Publications
Lung cancer, with the highest morbidity and second highest death rates, is one of the most common cancers in both males and females worldwide. Lung adenocarcinoma (LAD) is the main lung cancer class. KCNQ1 Opposite Strand/Antisense Transcript 1 (KCNQ1OT1) gene is an lncRNA which had been reported high-expression in colorectal cancer. In this study, the expression of KCNQ1OT1 was confirmed to be highly expressed in LAD tissues and cells contrast to control tissues and cells, and high KCNQ1OT1 expression correlated to malignant behaviors of LAD, including big tumor size, poor differentiation, positive lymphatic metastasis and high TNM stages. The transfection of si-KCNQ1OT1 could effectually knockdown the expression of KCNQ1OT1 in A549 and A549/PA cells. The KCNQ1OT1 knockdown depressed the proliferation and invasion of A549 cells, and advanced cellular apoptosis of A549 cells. The expression of KCNQ1OT1 in LAD patients insensitive to paclitaxel was much higher than that in LAD patients sensitive to paclitaxel; the KCNQ1OT1 expression in A549/PA cells was also much higher than that in control A549 cells. The half maximal inhibitory concentration (IC50) of paclitaxel in A549/PA cells was depressed by KCNQ1OT1 knockdown, chemoresistance of A549/PA cells was inhibited significantly. KCNQ1OT1 knockdown also depressed the expression of multidrug resistance 1 (MDR1) protein in A549/PA cells. In summary, lncRNA KCNQ1OT1 was highly expressed in LAD and functioned as a potential oncogene to inhibit malignancy and chemoresistance of LAD cells, which might be a novel potential therapeutic target for LAD.

Brioude F, Nicolas C, Marey I, et al.
Hypercortisolism due to a Pituitary Adenoma Associated with Beckwith-Wiedemann Syndrome.
Horm Res Paediatr. 2016; 86(3):206-211 [PubMed] Related Publications
BACKGROUND: Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome with an increased risk of cancer. Most BWS patients show a molecular defect in the 11p15 region that contains imprinted genes. BWS has been associated with malignant neoplasms during infancy. Descriptions of benign tumors, especially in adult patients, are rarer.
METHODS/RESULTS: We report the case of a BWS patient with pituitary adenoma caused by loss of methylation (LOM) at ICR2 (locus CDKN1C/KCNQ1OT1). The patient was referred to an endocrinology unit for suspicion of Cushing's disease due to a history of macroglossia and hemihyperplasia. Biological tests led to the diagnosis of ACTH-dependent hypercortisolism. MRI showed a microadenoma of the pituitary gland, confirming the diagnosis of Cushing's disease. DNA methylation analysis revealed LOM at ICR2 that was in a mosaic state in the patient's leukocytes, but was present in nearly all cells of the pituitary adenoma. The epigenetic defect was associated with a somatic USP8 mutation in the adenoma.
CONCLUSION: Pituitary adenoma rarely occurs in patients with BWS. However, BWS should be considered in cases of pituitary adenoma with minor and/or major signs of BWS. The association between ICR2 LOM and USP8 mutation in the adenoma is questionable. © 2016 S. Karger AG, Basel.

Andresini O, Ciotti A, Rossi MN, et al.
A cross-talk between DNA methylation and H3 lysine 9 dimethylation at the KvDMR1 region controls the induction of Cdkn1c in muscle cells.
Epigenetics. 2016; 11(11):791-803 [PubMed] Free Access to Full Article Related Publications
The cdk inhibitor p57

Piersigilli F, Auriti C, Mondì V, et al.
Decreased CDKN1C Expression in Congenital Alveolar Rhabdomyosarcoma Associated with Beckwith-Wiedemann Syndrome.
Indian J Pediatr. 2016; 83(12-13):1476-1478 [PubMed] Related Publications
The Beckwith-Wiedemann syndrome (BWS) is a genetic disorder characterized by somatic overgrowth and predisposition to embryonal tumors, such as Wilm's tumor, hepatoblastoma, neuroblastoma and rhabdomyosarcoma (RMS). BWS is associated with various genetic alterations: a variety of molecular lesions are described on the chromosome 11p15, affecting gene expression for IGF2, H19, CDKN1C and KCNQ1OT1. Alveolar RMS also recognises characteristic genetic alterations: two types of translocations, t(2,13) or t(1,13), that generate the PAX3-FKHR or PAX7-FKHR fusion proteins. It has been postulated however, that in BWS this kind of tumor occurs without this characteristic chromosomal rearrangement. The authors describe case of a neonate with BWS that presented at birth with cutaneous metastasis due to alveolar RMS. Genetic analysis showed lack of the two characteristic translocations in the tumor tissue, supporting a different oncogenic pathway of alveolar RMS in children with BWS.

Wang WC, Lai YC
Genetic analysis results of mature cystic teratomas of the ovary in Taiwan disagree with the previous origin theory of this tumor.
Hum Pathol. 2016; 52:128-35 [PubMed] Related Publications
The most accepted theory regarding mature cystic teratomas of the ovary is that they are of parthenogenetic origin from oocyte after the completion of first division. Our previous study demonstrated that the origin of mature cystic teratoma of the uterus is not related to the parthenogenetic process, but is most likely pluripotential stem cell or primordial germ cell before meiosis I. Further studies are needed to clarify the origin of benign mature cystic teratomas of the ovary in Taiwan. In the present study, we investigated the DNA profiles of 9 mature cystic teratomas of the ovary using short tandem repeat analysis with AmpFLSTR SGM Plus, Profiler PCR amplification kits. The methylation statuses of the HhaI sites in the SNRPN, H19DMR, and KvDMR regions were determined on methylation-sensitive multiplex ligation-dependent probe amplification analysis. DNA profiling data from the 9 mature cystic teratomas of the ovary excluded parthenogenetic origin, as most of the 15 short tandem repeat loci were heterozygous on genotyping. There were varying degrees of hypermethylation of SNRPN gene and KvDMR locus in the presence of maternal uniparental disomy in all 9 mature cystic teratomas of the ovary. In light of these results, we further postulated that the origin of these mature cystic teratomas of the ovary is oogonia or primary oocyte before germinal vesicle stage failure of meiosis I.

Sunamura N, Ohira T, Kataoka M, et al.
Regulation of functional KCNQ1OT1 lncRNA by β-catenin.
Sci Rep. 2016; 6:20690 [PubMed] Free Access to Full Article Related Publications
Long noncoding RNAs (lncRNAs) have been implicated in many biological processes through epigenetic mechanisms. We previously reported that KCNQ1OT1, an imprinted antisense lncRNA in the human KCNQ1 locus on chromosome 11p15.5, is involved in cis-limited silencing within an imprinted KCNQ1 cluster. Furthermore, aberration of KCNQ1OT1 transcription was observed with a high frequency in colorectal cancers. However, the molecular mechanism of the transcriptional regulation and the functional role of KCNQ1OT1 in colorectal cancer remain unclear. Here, we show that the KCNQ1OT1 transcriptional level was significantly increased in human colorectal cancer cells in which β-catenin was excessively accumulated in the nucleus. Additionally, overexpression of β-catenin resulted in an increase in KCNQ1OT1 lncRNA-coated territory. On the other hand, knockdown of β-catenin resulted in significant decrease of KCNQ1OT1 lncRNA-coated territory and an increase in the mRNA expression of the SLC22A18 and PHLDA2 genes that are regulated by KCNQ1OT1. We showed that β-catenin can promote KCNQ1OT1 transcription through direct binding to the KCNQ1OT1 promoter. Our evidence indicates that β-catenin signaling may contribute to development of colorectal cancer by functioning as a novel lncRNA regulatory factor via direct targeting of KCNQ1OT1.

Yoshizawa S, Fujiwara K, Sugito K, et al.
Pyrrole-imidazole polyamide-mediated silencing of KCNQ1OT1 expression induces cell death in Wilms' tumor cells.
Int J Oncol. 2015; 47(1):115-21 [PubMed] Related Publications
KvDMR (an intronic CpG island within the KCNQ1 gene) is one of the imprinting control regions on human chromosome 11p15.5. Since KvDMR exists within the promoter region of KCNQ1OT1 (antisense transcript of KCNQ1), it is likely that genomic alterations of this region including deletion, paternal uniparental disomy and de-methylation in maternal allele lead to aberrant overexpression of KCNQ1OT1. Indeed, de-methylation of KvDMR accompanied by uncontrolled overexpression of KCNQ1OT1 occurs frequently in Beckwith-Wiedemann syndrome (BWS), and around 10% of BWS patients developed embryonal tumors (Wilms' tumor or hepatoblastoma). These observations strongly suggest that silencing of KCNQ1OT1 expression might suppress its oncogenic potential. In the present study, we designed two pyrrole-imidazole (PI) polyamides, termed PI-a and PI-b, which might have the ability to bind to CCAAT boxes of the KCNQ1OT1 promoter region, and investigated their possible antitumor effect on Wilms' tumor-derived G401 cells. Gel retardation assay demonstrated that PI-a and PI-b specifically bind to their target sequences. Microscopic observations showed the efficient nuclear access of these PI polyamides. Quantitative real-time PCR analysis revealed that the expression level of KCNQ1OT1 was significantly decreased when treated with PI-a and PI-b simultaneously but not with either PI-a or PI-b single treatment. Consistent with these results, the combination of PI-a and PI-b resulted in a significant reduction in viability of G401 cells in a dose-dependent manner. Furthermore, FACS analysis demonstrated that combinatory treatment with PI-a and PI-b induces cell death as compared with control cells. Taken together, our present observations strongly suggest that the combinatory treatment with PI polyamides targeting KCNQ1OT1 might be a novel therapeutic strategy to cure patients with tumors over-expressing KCNQ1OT1.

Ribarska T, Goering W, Droop J, et al.
Deregulation of an imprinted gene network in prostate cancer.
Epigenetics. 2014; 9(5):704-17 [PubMed] Free Access to Full Article Related Publications
Multiple epigenetic alterations contribute to prostate cancer progression by deregulating gene expression. Epigenetic mechanisms, especially differential DNA methylation at imprinting control regions (termed DMRs), normally ensure the exclusive expression of imprinted genes from one specific parental allele. We therefore wondered to which extent imprinted genes become deregulated in prostate cancer and, if so, whether deregulation is due to altered DNA methylation at DMRs. Therefore, we selected presumptive deregulated imprinted genes from a previously conducted in silico analysis and from the literature and analyzed their expression in prostate cancer tissues by qRT-PCR. We found significantly diminished expression of PLAGL1/ZAC1, MEG3, NDN, CDKN1C, IGF2, and H19, while LIT1 was significantly overexpressed. The PPP1R9A gene, which is imprinted in selected tissues only, was strongly overexpressed, but was expressed biallelically in benign and cancerous prostatic tissues. Expression of many of these genes was strongly correlated, suggesting co-regulation, as in an imprinted gene network (IGN) reported in mice. Deregulation of the network genes also correlated with EZH2 and HOXC6 overexpression. Pyrosequencing analysis of all relevant DMRs revealed generally stable DNA methylation between benign and cancerous prostatic tissues, but frequent hypo- and hyper-methylation was observed at the H19 DMR in both benign and cancerous tissues. Re-expression of the ZAC1 transcription factor induced H19, CDKN1C and IGF2, supporting its function as a nodal regulator of the IGN. Our results indicate that a group of imprinted genes are coordinately deregulated in prostate cancers, independently of DNA methylation changes.

Jiang YJ, Bikle DD
LncRNA profiling reveals new mechanism for VDR protection against skin cancer formation.
J Steroid Biochem Mol Biol. 2014; 144 Pt A:87-90 [PubMed] Related Publications
Accumulating evidence strongly suggests a protective role of vitamin D signaling against chemical and UVR-induced skin cancer formation. However, the mechanism remains largely unknown. Recently, the emerging role of long, non-coding RNA (lncRNA) as a hallmark of cancer has become better appreciated. LncRNAs are mRNA-like transcripts ranging in length from 200 bases to 100kb lacking significant open reading frames, which are involved in a broad spectrum of tumorigenic/metastatic processes. In this study we profiled 90 well-annotated mouse lncRNAs from cultured mouse keratinocytes after deleting the vitamin D receptor (VDR) (∼90%) vs. control cells using an lncRNA array analysis. We found that several well-known oncogenes, including H19, HOTTIP and Nespas, are significantly increased (6.3-1.8-fold), whereas tumor suppressors (Kcnq1ot1, lincRNA-p21) are decreased (up to 50-70%) in VDR deleted keratinocytes. A similar pattern of lncRNA profiling is observed in the epidermis of K14 driven, tamoxifen-regulated epidermal-specific VDR null vs. wild-type control mice. Additionally there is an increase in the expression levels of other oncogenes (mHOTAIR, Malat1 and SRA) and a decrease of other tumor suppressors (Foxn2-as, Gtl2-as, H19-as). The increased expression levels of HOTTIP and H19 were further confirmed by real-time PCR analysis with individually designed primer sets. The major finding of this study is a novel mechanism for protection by VDR against skin cancer formation by maintaining the balance of oncogenic to tumor suppressing lncRNAs. In keratinocytes lacking VDR this balance is disturbed with increased expression of oncogenes and decreased expression of tumor suppressors, a mechanism that predisposes the VDR deficient mice to skin cancer formation. This article is part of a Special Issue entitled "Vitamin D Workshop".

Wan J, Huang M, Zhao H, et al.
A novel tetranucleotide repeat polymorphism within KCNQ1OT1 confers risk for hepatocellular carcinoma.
DNA Cell Biol. 2013; 32(11):628-34 [PubMed] Related Publications
KCNQ1 overlapping transcript 1 (KCNQ1OT1), a long noncoding RNA responsible for silencing a cluster of genes in cis, has been shown to be involved in multiple cancers. However, much remains unclear of how KCNQ1OT1 contributes to carcinogenesis. By thoroughly analyzing 510 hepatocellular carcinoma (HCC) cases and 1014 healthy controls in a Chinese population, we identified a novel short tandem repeat (STR) polymorphism (rs35622507) within the KCNQ1OT1 coding region and evaluated its association with HCC susceptibility. Logistic regression analysis showed that compared with individuals carrying the homozygote 10-10 genotype, those heterozygote subjects who carry only one allele 10 had a significantly decreased risk of HCC (adjusted odds ratio [OR]=0.67, 95% confidence interval [CI]=0.53-0.86, p=0.0009), with the risk decreased even further in those without allele 10 (adjusted OR=0.38, 95% CI=0.21-0.69, p=0.0005). Furthermore, genotype-phenotype correlation studies using four hepatoma cell lines support a significant association between STR genotypes and the expression of KCNQ1OT1. Cell lines without allele 10 conferred a 20.9-33.3-fold higher expression of KCNQ1OT1. Meanwhile, KCNQ1OT1 expression was reversely correlated with the expression of the cyclin-dependent kinase inhibitor 1C (CDKN1C), a tumor suppressor gene located within the CDKN1C/KCNQ1OT1 imprinted region, in three hepatoma cell lines. Finally, in silico prediction suggested that different alleles could alter the local structure of KCNQ1OT1. Taken together, our findings suggest that the STR polymorphism within KCNQ1OT1 contributes to hepatocarcinogenesis, possibly by affecting KCNQ1OT1 and CDKN1C expression through a structure-dependent mechanism. The replication of our studies and further functional studies are needed to validate our hypothesis and understand the roles of KCNQ1OT1 polymorphisms in predisposition for HCC.

Sidhu A, Debelenko L, Misra VK
Infantile adrenocortical tumor with an activating GNAS1 mutation.
J Clin Endocrinol Metab. 2013; 98(1):E115-8 [PubMed] Related Publications
CONTEXT: Pediatric adrenocortical tumors (ACTs) are rare and are frequently associated with tumor predisposition syndromes. Somatic GNAS1 mutations are associated with adrenocortical hyperplasia, but have not typically been reported in ACTs.
OBJECTIVE: We report on genetic and histopathological findings in a 3-month-old infant presenting with a unilateral cortisol-producing ACT with malignant features.
METHODS: We performed a detailed clinical evaluation of the patient along with molecular genetic testing of genes associated with ACTs in both tumor tissue and peripheral lymphocytes. We also performed a histopathological analysis of the tumor tissue.
RESULTS: The patient was found to have a p.R201C-activating mutation in exon 8 of the GNAS1 gene in adrenocortical tumor tissue but not peripheral lymphocytes. This mutation is the characteristic genetic change in McCune-Albright syndrome. In contrast to previously reported GNAS1-positive tumors characterized by bimodal diffuse and nodular adrenocortical hypertrophy, our patient had a single adrenocortical mass that showed features of malignancy, including areas of necrosis, microcystic degeneration, and venous and capsular microinvasion-changes that have been seen previously in Beckwith-Wiedemann syndrome. However, our patient did not have clinical features of Beckwith-Wiedemann syndrome. Further analysis revealed abnormal allele-specific hypomethylation of the KCNQ1OT1 gene in the tumor sample but not peripheral lymphocytes.
CONCLUSION: This is a novel case of an activating GNAS1 mutation associated with an epigenetic alteration that may be related to adrenocortical tumorigenesis. Our findings may have implications in the molecular pathogenesis of pediatric ACTs.

Kitagawa M, Kotake Y, Ohhata T
Long non-coding RNAs involved in cancer development and cell fate determination.
Curr Drug Targets. 2012; 13(13):1616-21 [PubMed] Related Publications
The possible physiological significance of long non-coding RNAs (lncRNAs) has only recently been recognized. Technical innovations such as the super high-resolution tiling array and deep sequencing technology have indicated their importance. It has been proposed that lncRNAs such as HOTAIR are involved in the recruitment of chromatin modifiers to the target genes. The lncRNA ANRIL has been reported to be associated with a Polycomb complex, recruiting it to the target gene INK4 locus where it suppresses transcription via histone modification. Other lncRNAs such as Kcnq1ot1, AIR and Xist have also been found to recruit chromatin modifiers to their target loci. In this review, we discuss the function of lncRNAs such as HOTAIR, ANRIL, Kcnq1ot1, and Xist which recruit chromatin modifiers to target genes and discuss their involvement in cancer development and aggressiveness, and other cell fate determination.

Wijnen M, Alders M, Zwaan CM, et al.
KCNQ1OT1 hypomethylation: a novel disguised genetic predisposition in sporadic pediatric adrenocortical tumors?
Pediatr Blood Cancer. 2012; 59(3):565-6 [PubMed] Related Publications
Pediatric adrenal tumors, other than neuroblastoma, are rare and can be associated with a genetic predisposition. In this report we describe two patients with an isolated and apparently sporadic adrenocortical tumor; one girl with a carcinoma, the other girl with an adenoma. In both patients genetic screening revealed hypomethylation of the KCNQ1OT1 gene, well-known for its association with the Beckwith-Wiedemann syndrome. This represents a likely novel genetic predisposition in patients with adrenocortical tumors without clear phenotypic features of the Beckwith-Wiedemann syndrome.

Rodriguez BA, Weng YI, Liu TM, et al.
Estrogen-mediated epigenetic repression of the imprinted gene cyclin-dependent kinase inhibitor 1C in breast cancer cells.
Carcinogenesis. 2011; 32(6):812-21 [PubMed] Free Access to Full Article Related Publications
While tumor suppressor genes frequently undergo epigenetic silencing in cancer, how the instructions directing this transcriptional repression are transmitted in cancer cells remain largely unclear. Expression of cyclin-dependent kinase inhibitor 1C (CDKN1C), an imprinted gene on chromosomal band 11 p15.5, is reduced or lost in the majority of breast cancers. Here, we report that CDKN1C is suppressed by estrogen through epigenetic mechanisms involving the chromatin-interacting noncoding RNA KCNQ1OT1 and CCCTC-binding factor (CTCF). Activation of estrogen signaling reduced CDKN1C expression 3-fold (P < 0.001) and established repressive histone modifications at the 5' regulatory region of the locus. These events were concomitant with induction of KCNQ1OT1 expression as well as increased recruitment of CTCF to both the distal KCNQ1OT1 promoter-associated imprinting control region (ICR) and the CDKN1C locus. Transient depletion of CTCF by small interfering RNA increased CDKN1C expression and significantly reduced the estrogen-mediated repression of CDKN1C. Further studies in breast cancer cell lines indicated that the epigenetic silencing of CDKN1C occurs in part as the result of genetic loss of the inactive methylated 11p15.5 ICR allele (R(2) = 0.612, P < 0.001). We also found a novel cis-encoded antisense transcript, CDKN1C-AS, which is induced by estrogen signaling following pharmacologic inhibition of DNA methyltransferase and histone deacetylase activity. Forced expression of CDKN1C-AS was capable of repressing endogenous CDKN1C in vivo. Our findings suggest that in addition to promoter hypermethylation, epigenetic repression of tumor suppressor genes by CTCF and noncoding RNA transcripts could be more common and important than previously understood.

Perlman EJ, Grundy PE, Anderson JR, et al.
WT1 mutation and 11P15 loss of heterozygosity predict relapse in very low-risk wilms tumors treated with surgery alone: a children's oncology group study.
J Clin Oncol. 2011; 29(6):698-703 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Children's Oncology Group defines very low-risk Wilms tumors (VLRWT) as stage I favorable histology Wilms tumors weighing less than 550 g in children younger than 24 months of age. VLRWTs may be treated with nephrectomy alone. However, 10% to 15% of VLRWTs relapse without chemotherapy. Previous studies suggest that VLRWTs with low WT1 expression and/or 11p15 loss of heterozygosity (LOH) may have increased risk of relapse. The current study validates these findings within prospectively identified children with VLRWT who did not receive adjuvant chemotherapy.
PATIENTS AND METHODS: Fifty-six VLRWTs (10 relapses) were analyzed for mutation of WT1, CTNNB1, and WTX; for 11p15 LOH using microsatellite analysis; and for H19DMR and KvDMR1 methylation.
RESULTS: 11p15 LOH was identified in 19 (41%) of 46 evaluable VLRWTs and was significantly associated with relapse (P < .001); 16 of 19 were isodisomic for 11p15. WT1 mutation was identified in nine (20%) of 45 evaluable VLRWTs and was significantly associated with relapse (P = .004); all nine cases also had 11p15 LOH. All evaluable tumors showing LOH by microsatellite analysis also showed LOH by methylation analysis. Retention of the normal imprinting pattern was identified in 24 of 42 evaluable tumors, and none relapsed. Loss of imprinting at 11p15 was identified in one of 42 tumors.
CONCLUSION: WT1 mutation and 11p15 LOH are associated with relapse in patients with VLRWTs who do not receive chemotherapy. These may provide meaningful biomarkers to stratify patients for reduced chemotherapy in the future. VLRWTs show a different incidence of WT1 mutation and 11p15 imprinting patterns than has been reported in Wilms tumors of all ages.

Clericuzio CL, Martin RA
Diagnostic criteria and tumor screening for individuals with isolated hemihyperplasia.
Genet Med. 2009; 11(3):220-2 [PubMed] Free Access to Full Article Related Publications
Isolated hemihyperplasia, formerly termed isolated hemihypertrophy, is a congenital overgrowth disorder associated with an increased risk for embryonal tumors, mainly Wilms tumor and hepatoblastoma. This practice guideline will set forth the diagnostic criteria and tumor screening recommendations for children with isolated hemihyperplasia, based on the best information available. There is clinical overlap between isolated hemihyperplasia with Beckwith-Wiedemann syndrome. The majority of Beckwith-Wiedemann syndrome patients have a molecular abnormality involving the imprinted cluster of genes at 11p15.5. In contrast, the preponderance of isolated hemihyperplasia patients studied have no identified etiology. Tumors have developed in isolated hemihyperplasia patients with and without molecular abnormalities. For this reason, molecular diagnostics are not helpful in identifying the subset of isolated hemihyperplasia patients with tumor risk and all isolated hemihyperplasia patients should undergo tumor screening.

Alsultan A, Lovell MA, Hayes KL, et al.
Simultaneous occurrence of right adrenocortical tumor and left adrenal neuroblastoma in an infant with Beckwith-Wiedemann syndrome.
Pediatr Blood Cancer. 2008; 51(5):695-8 [PubMed] Related Publications
Children with Beckwith-Wiedemann syndrome (BWS) have increased risk for development of embryonal tumors. We present the case of an infant with BWS who has hypomethylation of LIT1 gene in the 11p15.5 chromosomal region and at 6 months of age presented with simultaneous occurrence of neuroblastoma arising from the left adrenal gland and a right adrenocortical tumor. She underwent surgical resection of both tumors and remains tumor free 18 months after surgery.

Kou YC, Shao L, Peng HH, et al.
A recurrent intragenic genomic duplication, other novel mutations in NLRP7 and imprinting defects in recurrent biparental hydatidiform moles.
Mol Hum Reprod. 2008; 14(1):33-40 [PubMed] Related Publications
A complete hydatidiform mole (CHM) is an abnormal pregnancy with hyperproliferative vesicular trophoblast and no fetal development. Most CHM are sporadic and androgenetic, but recurrent HM have biparental inheritance (BiHM) with disrupted DNA methylation at differentially methylated regions (DMRs) of imprinted loci. Some women with recurrent BiHM have mutations in the NLRP7 gene on chromosome 19q13.42. Using bisulfite genomic sequencing at eight imprinted DMRs on DNA from two BiHMs, we found a pattern of failure to acquire or maintain DNA methylation at DMRs (PEG3, SNRPN, KCNQ1OT1, GNAS exon 1A) that normally acquire CpG methylation during oogenesis, but not at H19, which acquires CpG methylation during spermatogenesis. Secondary imprints at the GNAS locus showed variable abnormal patterns with both gain and loss of CpG methylation. We found novel missense and splice-site mutations in NLRP7 in women with non-familial recurrent BiHM. We identified and characterized a homozygous intragenic tandem duplication including exons 2 through 5 of NLRP7 that results in a predicted truncated protein in affected women of three unrelated Egyptian kindreds, suggesting a founder effect. Our findings firmly establish that NLRP7 mutations are a major cause of BiHM and confirm presence of a complex pattern of imprinting abnormalities in BiHM tissues.

Kim KP, Thurston A, Mummery C, et al.
Gene-specific vulnerability to imprinting variability in human embryonic stem cell lines.
Genome Res. 2007; 17(12):1731-42 [PubMed] Free Access to Full Article Related Publications
Disregulation of imprinted genes can be associated with tumorigenesis and altered cell differentiation capacity and so could provide adverse outcomes for stem cell applications. Although the maintenance of mouse and primate embryonic stem cells in a pluripotent state has been reported to disrupt the monoallelic expression of several imprinted genes, available data have suggested relatively higher imprint stability in the human equivalents. Identification of 202 heterozygous loci allowed us to examine the allelic expression of 22 imprinted genes in 22 human embryonic stem cell lines. Half of the genes examined (IPW, H19, MEG3, MEST isoforms 1 and 2, PEG10, MESTIT1, NESP55, ATP10A, PHLDA2, IGF2) showed variable allelic expression between lines, indicating vulnerability to disrupted imprinting. However, seven genes showed consistent monoallelic expression (NDN, MAGEL2, SNRPN, PEG3, KCNQ1, KCNQ1OT1, CDKN1C). Furthermore, four genes known to be monoallelic or to exhibit polymorphic imprinting in later-developing human tissues (TP73, IGF2R, WT1, SLC22A18) were always biallelic in hESCs. MEST isoform 1, PEG10, and NESP55 showed an association between the variability observed in interline allelic expression status and the DNA methylation of previously identified regulatory regions. Our results demonstrate gene-specific differences in the stability of imprinted loci in human embryonic stem cells and identify disrupted DNA methylation as one potential mechanism. We conclude the prudence of including comprehensive imprinting analysis in the continued characterization of human embryonic stem cell lines.

Bjornsson HT, Brown LJ, Fallin MD, et al.
Epigenetic specificity of loss of imprinting of the IGF2 gene in Wilms tumors.
J Natl Cancer Inst. 2007; 99(16):1270-3 [PubMed] Free Access to Full Article Related Publications
Loss of imprinting (LOI) of the IGF2 gene (which encodes insulin-like growth factor II) is the most common genetic or epigenetic alteration in Wilms tumor; LOI involves aberrant activation of the normally repressed maternally inherited allele. We found previously that LOI of IGF2 occurs in approximately half of all Wilms tumors (i.e., those arising from lineage-committed nephrogenic progenitor cells). We investigated whether LOI of IGF2 is associated with relaxation of imprinting at loci other than IGF2 or with widespread alterations in DNA methylation. We stratified 59 Wilms tumor samples by IGF2 LOI status by use of hot-stop reverse transcription-polymerase chain reaction and/or methylation analysis of the differentially methylated region of the H19 gene and identified 31 samples with and 28 without LOI. We used quantitative allele-specific expression analysis to determine whether six other imprinted genes (i.e., H19, KCNQ1, LIT1, TSSC5, GRB10, and MEG3) had subtle LOI. No statistically significant difference in allele-specific expression between Wilms tumor with or without LOI was found for LIT1, TSSC5, GRB10, and MEG3. For the KCNQ1 gene there was a slight difference between the groups with (37.0%, 95% confidence interval [CI] = 31.8% to 42.2%) and without (27.7%, 95% CI = 21.8% to 33.5%) LOI (P = .02 for F test of group differences in a mixed-effects model). For H19, we also found a slight difference between the groups with (7.5%, 95% CI = 2.4% to 12.7%) and without (2.2%, 95% CI = -3.2% to 7.6%) LOI of IGF2 (P = .15 for F test). In 27 tumor samples, we also used a microarray technique to analyze methylation of 378 genes, 38 of which were suspected or confirmed imprinted genes. We found that statistically significant alterations in only the differentially methylated region of the H19 gene were associated with LOI of IGF2. Thus, epigenetic alterations in Wilms tumors are not widespread, supporting the gene and lineage specificity of LOI of IGF2.

Nakano S, Murakami K, Meguro M, et al.
Expression profile of LIT1/KCNQ1OT1 and epigenetic status at the KvDMR1 in colorectal cancers.
Cancer Sci. 2006; 97(11):1147-54 [PubMed] Related Publications
The human chromosome region 11p15.5 contains a number of maternally and paternally imprinted genes, and the LIT1/KCNQ1OT1 locus acts as an imprinting center in the proximal domain of 11p15.5. Loss of imprinting (LOI) of LIT1 and its correlation with methylation status at a differentially methylated region, the KvDMR1, were investigated in 69 colorectal cancer tissue specimens. LIT1 expression profiles were also examined by RNA-fluorescence in situ hybridization in 13 colorectal cancer cell lines. In 69 colorectal cancer tissue specimens, LOI of LIT1 was observed in nine of the 17 (53%) informative cases. Moreover, LOI of LIT1 was only observed in tumor samples. In the cell lines, methylation status at the KvDMR1 correlated well with LIT1 expression profiles. Loss of expression of LIT1 also correlated with enrichment of H3 lysine 9 (H3-K9) dimethylation and reduction of H3 lysine 4 (H3-K4) dimethylation. Thus, LIT1 expression appears to be controlled by epigenetic modifications at the KvDMR1, although CDKN1C expression, which is considered to be controlled by LIT1, was not associated with epigenetic status at the KvDMR1 in some colorectal cancer cell lines. Therefore, these findings suggest that LOI of LIT1 via epigenetic disruption plays an important role in colorectal carcinogenesis, but it is not necessarily associated with CDKN1C expression.

Satoh Y, Nakadate H, Nakagawachi T, et al.
Genetic and epigenetic alterations on the short arm of chromosome 11 are involved in a majority of sporadic Wilms' tumours.
Br J Cancer. 2006; 95(4):541-7 [PubMed] Free Access to Full Article Related Publications
Wilms' tumour is one of the most common solid tumours of childhood. 11p13 (WT1 locus) and 11p15.5 (WT2 locus) are known to have genetic or epigenetic aberrations in these tumours. In Wilms' tumours, mutation of the Wilms tumour 1 (WT1) gene at the WT1 locus has been reported, and the WT2 locus, comprising the two independent imprinted domains IGF2/H19 and KIP2/LIT1, can undergo maternal deletion or alterations associated with imprinting. Although these alterations have been identified in many studies, it is still not clear how frequently combined genetic and epigenetic alterations of these loci are involved in Wilms' tumours or how these alterations occur. To answer both questions, we performed genetic and epigenetic analyses of these loci, together with an additional gene, CTNNB1, in 35 sporadic Wilms' tumours. Loss of heterozygosity of 11p15.5 and loss of imprinting of IGF2 were the most frequent genetic (29%) and epigenetic (40%) alterations in Wilms' tumours, respectively. In total, 83% of the tumours had at least one alteration at 11p15.5 and/or 11p13. One-third of the tumours had alterations at multiple loci. Our results suggest that chromosome 11p is not only genetically but also epigenetically critical for the majority of Wilms' tumours.

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