title: The long non-coding RNA 91H increases aggressive phenotype of breast cancer cells and up-regulates H19/IGF2 expression through epigenetic modifications.
abstract: Numerous genomic imprinting loci are regulated by long non-coding RNA (lncRNA). We have previously identified a new lncRNA at the H19/IGF2 locus transcribed in H19 antisense orientation and named 91H. This RNA is conserved among mammals. In mice, 91H regulates positively IGF2 expression from a novel promoter. However, in human the function of 91H at the H19/IGF2 locus remains largely undeciphered. Here, we observed that 91H, H19 and IGF2 are overexpressed in breast tumors. By using 91H-knockdown breast cancer cells, we demonstrated that 91H exerts oncogenic properties by promoting cell growth, migration and invasion as well as tumor growth in xenografted immunodeficient mouse model. Moreover, 91H-knockdown reduces the expression of H19 and IGF2 in breast cancer cells. By chromatin-immunoprecipitation and methylation studies, we found that 91H expression prevents histone and DNA methylation on the maternal allele at the H19/IGF2 locus. These results indicate that 91H, through epigenetic modifications, is responsible of the maintenance of H19/IGF2 genomic imprinting allowing the allele-specific expression of H19 and IGF2. Taken together, overexpression of 91H in breast cancer and 91H-induced epigenetic modifications on H19/IGF2 locus suggest that 91H may play essential role in breast cancer development. Further studies are needed to investigate their role in terms of diagnosis and therapeutic.
authors: INSERM U908, 59655 Villeneuve d'Ascq, France; University of Lille, 59655 Villeneuve d'Ascq, France.
authors: Constance
authors: C
authors: Vennin
authors: CNRS UMR 8161, 59021 Lille, France.
authors: Nathalie
authors: N
authors: Spruyt
authors: INSERM U908, 59655 Villeneuve d'Ascq, France; Centre Oscar Lambret, 59020 Lille, France.
authors: Yves-Marie
authors: YM
authors: Robin
authors: PLETHA, Institut Pasteur Lille, 59019 Lille, France.
authors: Thierry
authors: T
authors: Chassat
authors: INSERM U908, 59655 Villeneuve d'Ascq, France; University of Lille, 59655 Villeneuve d'Ascq, France.
authors: Xuefen
authors: X
authors: Le Bourhis
authors: INSERM U908, 59655 Villeneuve d'Ascq, France; University of Lille, 59655 Villeneuve d'Ascq, France. Electronic address: eric.adriaenssens@univ-lille1.fr.
authors: Eric
authors: E
authors: Adriaenssens
mesh_terms: D000368:Aged; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D018392:Genomic Imprinting; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics* / Q000378:metabolism; D016513:Mice, SCID; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D010641:Phenotype; D034622:RNA Interference; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden
chemical_list: C094335:H19 long non-coding RNA; C035170:IGF2 protein, human; D062085:RNA, Long Noncoding; C000621689:long non-coding RNA 91H, human; D007335:Insulin-Like Growth Factor II
keywords: Breast tumorigenesis; Genomic imprinting; H19 antisense; Long non-coding RNA