title: PIWI-interacting RNA 021285 is involved in breast tumorigenesis possibly by remodeling the cancer epigenome.
abstract: Although PIWI-interacting RNAs (piRNAs) account for the largest class of the small non-coding RNA superfamily, virtually nothing is known of their function in human carcinogenesis. Once thought to be expressed solely in the germ line where they safeguard the genome against transposon-induced insertional mutations, piRNAs are now believed to play an active role in somatic gene regulation through sequence-specific histone modification and DNA methylation. In the current study, we investigate the role of piRNA-021285 (piR-021285) in the regulation of the breast cancer methylome. Genotypic screening of a panel of single-nucleotide polymorphism (SNP)-containing piRNAs revealed a significant association between SNP rs1326306 G>T in piR-021285 and increased likelihood for breast cancer in a Connecticut-based population (441 cases and 479 controls). Given nascent but compelling evidence of piRNA-mediated gene-specific methylation in the soma, a genome-wide methylation screen was then carried out using wild type (WT) and variant piR-021285 mimic-transfected MCF7 cells to explore whether the observed association could be attributed in part to piR-021285-induced methylation at cancer-relevant genes. We found significant methylation differences at a number of experimentally implicated breast cancer-related genes, including attenuated 5' untranslated region (UTR)/first exon methylation at the proinvasive ARHGAP11A gene in variant mimic-transfected cells. Follow-up functional analyses revealed both concurrent increased ARHGAP11A mRNA expression and enhanced invasiveness in variant versus WT piR-021285 mimic-transfected breast cancer cell lines. Taken together, our findings demonstrate the first evidence supporting a role of piRNAs, a novel group of non-coding RNA, in human tumorigenesis via a piRNA-mediated epigenetic mechanism, which warrants further confirmation and investigation.
authors.affiliation: Department of Environmental Health Sciences, Yale University School of Public Health, New Haven, CT 06520, USA and Present Address: Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, CA 90095, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Fu
authors.affiliation: Department of Environmental Health Sciences, Yale University School of Public Health, New Haven, CT 06520, USA and.
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Jacobs
authors.affiliation: Department of Epidemiology, Tulane School of Public Health and Tropical Medicine and Tulane Cancer Center, New Orleans, LA 70112, USA.
authors.forename: Aaron E
authors.initials: AE
authors.lastname: Hoffman
authors.affiliation: Department of Environmental Health Sciences, Yale University School of Public Health, New Haven, CT 06520, USA and.
authors.forename: Tongzhang
authors.initials: T
authors.lastname: Zheng
authors.affiliation: Department of Environmental Health Sciences, Yale University School of Public Health, New Haven, CT 06520, USA and yong.zhu@yale.edu.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhu
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D063646:Carcinogenesis; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009361:Neoplasm Invasiveness / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D034741:RNA, Small Interfering / Q000235:genetics*; D058727:RNA, Small Untranslated / Q000235:genetics*
chemical_list: C000596803:ARHGAP11A protein, human; D020690:GTPase-Activating Proteins; D034741:RNA, Small Interfering; D058727:RNA, Small Untranslated