Dataset Information

Long Noncoding RNAs CUPID1 and CUPID2 Mediate Breast Cancer Risk at 11q13 by Modulating the Response to DNA Damage.

ABSTRACT: Breast cancer risk is strongly associated with an intergenic region on 11q13. We have previously shown that the strongest risk-associated SNPs fall within a distal enhancer that regulates CCND1. Here, we report that, in addition to regulating CCND1, this enhancer regulates two estrogen-regulated long noncoding RNAs, CUPID1 and CUPID2. We provide evidence that the risk-associated SNPs are associated with reduced chromatin looping between the enhancer and the CUPID1 and CUPID2 bidirectional promoter. We further show that CUPID1 and CUPID2 are predominantly expressed in hormone-receptor-positive breast tumors and play a role in modulating pathway choice for the repair of double-strand breaks. These data reveal a mechanism for the involvement of this region in breast cancer.

SUBMITTER: Betts JA

PROVIDER: S-EPMC5544418 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Long Noncoding RNAs CUPID1 and CUPID2 Mediate Breast Cancer Risk at 11q13 by Modulating the Response to DNA Damage.

Betts Joshua A JA Moradi Marjaneh Mahdi M Al-Ejeh Fares F Lim Yi Chieh YC Shi Wei W Sivakumaran Haran H Tropée Romain R Patch Ann-Marie AM Clark Michael B MB Bartonicek Nenad N Wiegmans Adrian P AP Hillman Kristine M KM Kaufmann Susanne S Bain Amanda L AL Gloss Brian S BS Crawford Joanna J Kazakoff Stephen S Wani Shivangi S Wen Shu W SW Day Bryan B Möller Andreas A Cloonan Nicole N Pearson John J Brown Melissa A MA Mercer Timothy R TR Waddell Nicola N Khanna Kum Kum KK Dray Eloise E Dinger Marcel E ME Edwards Stacey L SL French Juliet D JD

American journal of human genetics 20170801 2

Breast cancer risk is strongly associated with an intergenic region on 11q13. We have previously shown that the strongest risk-associated SNPs fall within a distal enhancer that regulates CCND1. Here, we report that, in addition to regulating CCND1, this enhancer regulates two estrogen-regulated long noncoding RNAs, CUPID1 and CUPID2. We provide evidence that the risk-associated SNPs are associated with reduced chromatin looping between the enhancer and the CUPID1 and CUPID2 bidirectional promot ...[more]

PMID: 28777932

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Project description:ObjectiveTo identify long noncoding RNAs (lncRNAs), including long intergenic noncoding RNAs (lincRNAs), antisense RNAs, and pseudogenes, associated with the inflammatory response in human primary osteoarthritis (OA) chondrocytes and to explore their expression and function in OA.MethodsOA cartilage was obtained from patients with hip or knee OA following joint replacement surgery. Non-OA cartilage was obtained from postmortem donors and patients with fracture of the neck of the femur. Primary OA chondrocytes were isolated by collagenase digestion. LncRNA expression analysis was performed by RNA sequencing (RNAseq) and quantitative reverse transcriptase-polymerase chain reaction. Modulation of lncRNA chondrocyte expression was achieved using LNA longRNA GapmeRs (Exiqon). Cytokine production was measured with Luminex.ResultsRNAseq identified 983 lncRNAs in primary human hip OA chondrocytes, 183 of which had not previously been identified. Following interleukin-1β (IL-1β) stimulation, we identified 125 lincRNAs that were differentially expressed. The lincRNA p50-associated cyclooxygenase 2-extragenic RNA (PACER) and 2 novel chondrocyte inflammation-associated lincRNAs (CILinc01 and CILinc02) were differentially expressed in both knee and hip OA cartilage compared to non-OA cartilage. In primary OA chondrocytes, these lincRNAs were rapidly and transiently induced in response to multiple proinflammatory cytokines. Knockdown of CILinc01 and CILinc02 expression in human chondrocytes significantly enhanced the IL-1-stimulated secretion of proinflammatory cytokines.ConclusionThe inflammatory response in human OA chondrocytes is associated with widespread changes in the profile of lncRNAs, including PACER, CILinc01, and CILinc02. Differential expression of CILinc01 and CIinc02 in hip and knee OA cartilage, and their role in modulating cytokine production during the chondrocyte inflammatory response, suggest that they may play an important role in mediating inflammation-driven cartilage degeneration in OA.

Project description:BACKGROUND:The landscape and biological functions of tumor suppressor long noncoding RNAs in breast cancer are still unknown. METHODS:Data from whole transcriptome sequencing of 33 breast specimens in the Harbin Medical University Cancer Center cohort and The Cancer Genome Atlas was applied to identify and validate the landscape of tumor suppressor long noncoding RNAs, which was further validated by The Cancer Genome Atlas pancancer data including 33 cancer types and 12,839 patients. Next, the expression model, prognostic roles, potential biological functions and epigenetic regulation of tumor suppressor long noncoding RNAs were investigated and validated in the breast cancer and pancancer cohorts. Finally, EPB41L4A-AS2 was selected to validate our novel finding, and the tumor suppressive roles of EPB41L4A-AS2 in breast cancer were examined. RESULTS:We identified and validated the landscape of tumor suppressor long noncoding RNAs in breast cancer. The expression of the identified long noncoding RNAs was downregulated in cancer tissue samples compared with normal tissue samples, and these long noncoding RNAs correlated with a favorable prognosis in breast cancer patients and the patients in the pancancer cohort. Multiple carcinogenesis-associated biological functions were predicted to be regulated negatively by these long noncoding RNAs. Moreover, these long noncoding RNAs were transcriptionally regulated by epigenetic modification, including DNA methylation and histone methylation modification. Finally, EPB41L4A-AS2 inhibited breast cancer cell proliferation, migration and invasion and induced cell apoptosis in vitro. Mechanistically, EPB41L4A-AS2, acting at least in part as a tumor suppressor, upregulated tumor suppressor gene expression. Moreover, ZNF217 recruited EZH2 to the EPB41L4A-AS2 locus and suppressed the expression of EPB41L4A-AS2 by epigenetically increasing H3K27me3 enrichment. CONCLUSIONS:This work enlarges the functional landscape of known long noncoding RNAs in human cancer and provides novel insights into the suppressive roles of these long noncoding RNAs.

Dataset Information

Long Noncoding RNAs CUPID1 and CUPID2 Mediate Breast Cancer Risk at 11q13 by Modulating the Response to DNA Damage.

Publications

Long Noncoding RNAs CUPID1 and CUPID2 Mediate Breast Cancer Risk at 11q13 by Modulating the Response to DNA Damage.

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