Between 70-80 % of human genome is transcribed, nevertheless it contains only 1.5% of protein-coding sequences while non-coding genome comprises almost 99%. Within the non-coding transcripts, a group of regulatory non-coding RNAs (ncRNAs) stands out in number: the long non-coding RNAs (lncRNAs), which are transcripts lacking coding potential and longer than 200 nucleotides. These transcripts are involved in different regulatory processes. In this study, our aim is to identify new lncRNAs involved in regulation of chromosomal instability (CIN) in a cell model of prostate cancer (PCa). Using RNA-seq data from two prostate cell lines: LNCaP (neoplastic, exhibits CIN) and PrEC (non-neoplastic, does not exhibit CIN) we have identified a lncRNA adjacent to the protein-coding gene RFC4, a gene involved in CIN in human cancers. This transcript, which we have provisionally named lncRNA-RFC4, exhibits differential expression between PrEC and LNCaP as seen in expression analyses from RNA-seq data. Afterwards, we performed qPCR experiments and found similar results as those seen in RNA-seq data analyses, lncRNA-RFC4 is downregulated in LNCaP, whereas the adjacent coding gene RFC4 is upregulated; the opposite is found in PrEC cell line. Western blot experiments confirmed that RFC4 protein abundance is higher in LNCaP. Our findings suggest that this transcript could have a possible repressor role on RFC4. In order to explore the regulatory mechanism, we performed cell fractionation and measured the abundance of lncRNA-RFC4 in each fraction using qPCR, we found that this transcript accumulates in the nucleus, specifically in the chromatin fraction, the nucleoplasm and cytoplasm fraction are not enriched with this lncRNA. In order to predict possible RNA-protein interactions we used an in-silico tool and found predicted interactions between lncRNA-RFC4 and two repressor proteins, CBX7 and SUZ12, part of the polycomb repressive complex 1 and 2 respectively, these interactions are yet to be confirmed experimentally. In conclusion, we have identified a chromatin-enriched lncRNA adjacent to RFC4, a CIN related gene, this ncRNA could play a repressive role on the adjacent gene though its interaction with the repressor proteins CBX7 and SUZ12, consequently, this transcript could be involved in a network controlling CIN in this cell model of PCa. Further experiments are needed to prove cis regulation of RFC4 by lncRNA-RFC4 and the molecular mechanism underlying this regulatory network. Citation Format: Rogelio Montiel Manriquez, Cristian Arriaga Canon, Laura Contreras Espinosa, Paula Alarcón Zendejas, Luis Alonso Herrera Montalvo. Identification of a regulatory long non-coding RNA adjacent to RFC4, a gene related to chromosomal instability, in a cell model of prostate cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3698.
In this study we aim to identify new lncRNAs, using RNA-seq data, and study whether those transcripts could be involved in chromosomal instability in prostate cancer and propose new possible RNA-based biomarkers. Using RNA-seq data from two prostate cell lines, neoplastic and non-neoplastic, we have identified a new lncRNA adjacent to CEP55, a gene associated with chromosomal instability. This lncRNA, which we have named lncRNA-CEP55, is 1.6 kb long and it is downregulated in the neoplastic cell line; this is also seen in the adjacent coding gene, CEP55, where the expression decreases in the neoplastic line, suggesting an important role of this transcript in carcinogenesis. This new lncRNA could be regulating CEP55 expression in these cell lines. Changes in expression of CEP55 have been associated to chromosomal instability and cancer development in colon cancer cell lines. Another lncRNA with differential expression in both cell lines has been identified, lncRNA-RFC4. This lncRNA has been reported before; it is an annotated gene in the human genome GRCh38/hg38, but it has not been studied in cancer. This lncRNA is highly expressed in the neoplastic cell line whereas its expression is very low in the non-neoplastic cell line. This lncRNA is 4.3 kb away from RFC4 (Replication Factor C Subunit 4), a protein coding gene related to mismatch repair and DNA double-strand break repair, which has been associated with chromosomal instability. lncRNA-RFC4 could be playing an important role in the cis regulation of RFC4 gene. lncRNA-CEP55 and lncRNA-RFC4 are important targets of study because of their differential expression in prostate cell lines (neoplastic and non-neoplastic). These lncRNAs could be playing an essential role in regulating the expression of the adjacent genes related to chromosomal instability, a enabling characteristic that facilitates the acquisition of the hallmarks of cancer. Citation Format: Rogelio Montiel Manriquez, Cristian Gabriel Oliverio Arriaga Canon, Fernanda Cisneros Soberanis, Carlo César Cortés, Inti Alberto De La Rosa Velazquez, Luis Alonso Herrera Montalvo. Identification of lncRNAs involved in regulation of chromosome instability-associated genes in a prostate cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2474.
Most of the human genome is transcribed into RNA, but only 2% encodes proteins, leading to a large group of non-coding RNA which, without constitutive RNA, is divided into 2 groups: small (sncRNA) and long (lncRNAs) non-coding RNAs. In this study we used RNA-seq data to identify new lncRNAs which could be involved in chromosomal instability (CIN) in prostate cancer (PCa). Our aim is to study their molecular mechanism and potential role as prognostic biomarkers in this disease. Using RNA-seq data from two prostate cell lines, neoplastic (LNCaP) and non-neoplastic (PrEC), we have identified an unannotated long lncRNA adjacent to CEP55 (centrosomal protein 55), a gene associated with CIN. We have named this 1.6 kb transcript as lncRNA- CEP55. qPCR experiments showed it is downregulated in the neoplastic cell line, in contrast to the adjacent coding gene, CEP55, which is upregulated in the same cell line and downregulated in PrEC. Our data suggest this new lncRNA might be a possible repressor for CEP55. Changes in expression of CEP55 have been associated to CIN in other cancer cell lines. LINC02043 is an annotated lncRNA. We identified a differential expression between PrEC and LNCaP using RNA-seq data. LINC02043 is adjacent to the protein-coding gene RFC4; this gene is associated with CIN in different human cancers. We performed qPCR experiments and found LINC02043 to be downregulated in LNCaP, whereas the adjacent coding gene RFC4 is upregulated; the opposite is found in PrEC cell line. Our findings suggest LINC02043 could have a possible repressor role in RFC4. This protein-coding gene is related to mismatch repair and DNA double-strand break repair, abnormalities in this coding gene have been associated with CIN in other cancer cell lines. LINC02043 could play an important role in the cis-regulation of RFC4. lncRNA-CEP55 and LINC02043 are important targets of study, these lncRNAs could play an essential role in regulating the expression of adjacent genes related to CIN, an enabling characteristic that facilitates the development of the hallmarks of cancer. Further analysis is needed to validate their mechanisms of action and their potential use as prognostic biomarkers in PCa. Particularly in PCa, CIN has lately been related to cancer progression. The role of lncRNAs as drivers of CIN in PCa is a promising field in order to understand PCa progression and may play a potential role as biomarkers in this disease. Citation Format: Rogelio Montiel Manriquez. Identification of long non-coding RNAs involved in chromosomal instability in a cellular model of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3574.
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