Abstract
Noncoding RNAs (ncRNAs), such as microRNAs and long noncoding RNAs (lncRNAs), participate in cellular transformation. Work done in the last decade has also demonstrated that ncRNAs with growth-inhibitory functions can undergo promoter CpG island hypermethylation-associated silencing in tumorigenesis. Herein, we wondered whether circular RNAs (circRNAs), a type of RNA transcripts lacking 5′-3′ ends and forming closed loops that are gaining relevance in cancer biology, are also a target of epigenetic inactivation in tumors. To tackle this issue, we have used cancer cells genetically deficient for the DNA methyltransferase enzymes in conjuction with circRNA expression microarrays. We have found that the loss of DNA methylation provokes a release of circRNA silencing. In particular, we have identified that promoter CpG island hypermethylation of the genes TUSC3 (tumor suppressor candidate 3), POMT1 (protein O-mannosyltransferase 1), ATRNL1 (attractin-like 1) and SAMD4A (sterile alpha motif domain containing 4A) is linked to the transcriptional downregulation of both linear mRNA and the hosted circRNA. Although some circRNAs regulate the linear transcript, we did not observe changes in TUSC3 mRNA levels upon TUSC3 circ104557 overexpression. Interestingly, we found circRNA-mediated regulation of target miRNAs and an in vivo growth inhibitory effect upon TUSC3 circ104557 transduction. Data mining for 5′-end CpG island methylation of TUSC3, ATRNL1, POMT1 and SAMD4A in cancer cell lines and primary tumors showed that the epigenetic defect was commonly observed among different tumor types in association with the diminished expression of the corresponding transcript. Our findings support a role for circRNA DNA methylation-associated loss in human cancer.
Highlights
Just 2% of the genome is transcribed into protein-coding RNAs [1], so the majority of transcripts are noncoding RNAs, that can be categorized according to their structural properties and length [2]
We took advantage of the development of an isogenic cell line obtained from the human colon cancer cell line HCT116, where the DNA methyltransferases 1 (DNMT1) and 3B (DNMT3B) genes have been genetically disrupted by homologous recombination [26]
We identified 18 circRNAs (0.36% of the total 4,998) that were not expressed in the colorectal cancer cell line HCT-116, but whose expression was restored in DKO cells and that were expressed in normal colorectal mucosa
Summary
Just 2% of the genome is transcribed into protein-coding RNAs [1], so the majority of transcripts are noncoding RNAs (ncRNAs), that can be categorized according to their structural properties and length [2]. The altered lncRNA expression of cancer cells can be associated with genetic events, such as copy number changes, but in an increasing number of cases, lncRNAs are targets of epigenetic silencing. In this regard, transcribed–ultraconserved regions [11, 12], small nucleolar RNAs [13], antisense RNAs [14] and other types of lncRNAs [15], have been demonstrated to undergo cancer-specific promoter CpG island hypermethylationassociated loss
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
