It is increasingly evident that non-coding RNAs play a significant role in tumour development. However, we still have a limited knowledge of the clinical significance of long non-coding RNAs (lncRNAs) in lung cancer. The FENDRR is a long coding RNA (also named FOXF1-AS1) located in the vicinity of the protein-coding gene FOXF1 at 16q24.1 chromosomal region. The present study aimed to define the clinic pathological significance of the long-non-coding RNA FENDRR in lung adenocarcinomas. FENDRR expression measured by quantitative PCR was found significantly downregulated (p<0.001) in lung adenocarcinoma samples in comparison with their normal adjacent tissues (n=70). RNA in situ hybridization (RNA-FISH) corroborated independently the down-regulation of FENDRR. Interestingly, the expression of FENDRR correlated positively (p<0.001) with the expression of its protein-coding neighbor gene FOXF1. Additionally, FOXF1 expression was also found downregulated in adenocarcinomas compared to normal samples (p<0.001) and its expression was significantly correlated with overall survival alone (p=0.003) or in combination with FENDRR expression (p=0.01). In conclusion, our data support that FENDRR and FOXF1 expression is decreased in lung adenocarcinoma and should be considered as new potential diagnostic/prognosis biomarkers.

We have been made aware of certain irregularities in Figures 1d, 2e, and 6b of the above work that are relevant to its results. We have been advised that, during the course of an internal inquiry and subsequent legal proceedings, corresponding author Dr. Susana Gonzalez was not able to provide original raw data or laboratory notes for any of the experiments represented in these figures to explain or justify the results reported in the article. The remaining co-authors maintain, and we accept, that they did not participate in, and nor were they aware of, this omission. We believe the foregoing constitutes a breach of certain representations and warranties made by the corresponding author Dr. Gonzalez to us with respect to complying with ethical standards and practices governing scientific research and conduct, and of our policy on publishing ethics and integrity. We note that we received, peer-reviewed, accepted, and published the article in good faith based on the purported veracity of these representations and warranties. We have been informed in our decisionmaking to retract the work by the guidance of COPE guidelines on retractions.

Long non-coding RNAs are known to play multiple roles in the complex machinery of the cell. However, their recent addition to genomic research has increased the complexity of gene expression analyses. In this work, we perform a computational study that aims to contribute to the current understanding of the mechanisms that underlie the experimentally suggested interaction between the lncRNA Fendrr and FoxF1 lung cancer tumor suppressor in carcinogenesis. Results suggest that there exists indeed a multi-level interaction between Fendrr and FoxF1 promoter region, both direct via RNA-DNA: DNA triplex domain formation or mediated by proteins that interact simultaneously with the promoter region of FoxF1 and Fendrr transcripts. Moreover, the applied computational methodology can serve as a pipeline to process any candidate lncRNA-gene pair of interest and obtain putative sources of lncRNA-gene interaction.

Pentacyclic triterpenes are natural substances, synthesized and present in variable amounts in a large number of terrestrial and aquatic plants, which act not only as antioxidants and antimicrobials but also as poisons, antibiotics, protease inhibitors, and so on. From the organic chemistry point of view, they are compounds derived from isoprene. These compounds consist of 30 carbons with different substituents, which facilitate their chemical identification and confer different physico-chemical and molecular properties. During the last ten years, most of them have been reported to have a variety of interesting and significant biological properties, such as analgesic, anti-allodynic, anti-diabetic, anti-oxidant, anti-parasitic, antimicrobial, anti-viral, anti-atherogenic, anti-inflammatory, anti-proliferative, anti-tumour, growth-stimulating activities as well as cardio- and neuro-protective activity. However, special attention has been focused on the study of their anti-tumour capacity, fundamentally, on the various molecular mechanisms involved in the induction of programmed cell death and the inhibition of metastatic activity, in different types of cancers. Researchers have also focused on the role that different RNA molecules play in the anti-tumour activity of the major triterpenes studied.

Preservation of hematopoietic hierarchy requires a constant and reciprocal interplay between chromatin-specific epigenetic regulators and lineage-modifying transcription factors. The polycomb member Bmi1 is a key factor in hematopoietic stem cell (HSC) maintenance, but its specific physiological role in subsequent hematopoietic lineage-specific commitments is unclear. Here, we generated conditional Bmi1 knockout (Bmi1-KO) mice. Selective ablation of Bmi1 in the hematopoietic system induced extensive upregulation of Ikaros and concomitant Ikaros-dependent lymphoid-lineage transcriptional priming, which is marked by their loss of H2A ubiquitination and increased H3K4 trimethylation in Bmi1-KO long-term HSCs (LT-HSCs). Removal of Ikaros in Bmi1-null LT-HSCs significantly diminished the hematopoietic defects seen in conditional Bmi1-KO mice. These alterations resulted in recovering the Bmi1-KO exhausted quiescent stem-cell pool, whereas the block in Bmi1-KO lymphoid-progenitor differentiation was rescued, allowing the development of mature lymphoid cells. Together, our results indicate that Ikaros is a critical Bmi1 target in vivo that prevents premature lineage specification of HSCs.

Polycomb group (PcG) proteins are key epigenetic regulators of hematopietic stem cell (HSC) fate. The PcG members Ezh2 and Ezh1 are important determinants of embryonic stem cell identity, and the transcript levels of these histone methyltransferases are inversely correlated during development. However, the role of Ezh1 in somatic stem cells is largely unknown. Here we show that Ezh1 maintains repopulating HSCs in a slow-cycling, undifferentiated state, protecting them from senescence. Ezh1 ablation induces significant loss of adult HSCs, with concomitant impairment of their self-renewal capacity due to a potent senescence response. Epigenomic and gene expression changes induced by Ezh1 deletion in senesced HSCs demonstrated that Ezh1-mediated PRC2 activity catalyzes monomethylation and dimethylation of H3K27. Deletion of Cdkn2a on the Ezh1 null background rescued HSC proliferation and survival. Our results suggest that Ezh1 is an important histone methyltransferase for HSC maintenance.

The ability of cancer cells to divide indefinitely whilst supporting tumor growth, metastasis and invasiveness resembles the behavior of stem cells. Here, we overview the role of Polycomb (PcG)-dependent epigenetic silencing mechanisms in stem cell biology and cancer, focusing on two major PcG components, Ezh2 and Bmi1. In a recent patent, stem cell PcG targets were shown to be more prone to cancer-specific promoter DNA methylation than non-targets, indicating that reversible PcG-mediated gene repression becomes replaced by permanent silencing. This epigenetic switching keeps the cell in a sustained state of self-renewal, predisposing it to tumorigenic transformation. These findings might provide the means of identifying the stem-cell epigenetic signatures associated with the origin of specific types of cancer. Based on the reversibility of epigenetic histone modifications, PcG proteins have become established targets in clinical practice for the treatment of a variety of cancers, notably treatments with histone deacetylase and methyltransferase inhibitors. A number of reports and patents highlight the potential of alternative approaches to targeting PcG for cancer therapy, including micro-RNA expression and the use of Hedgehog signaling pathway antagonists. The major shortcoming of current approaches is their lack of specificity. The identification of tumorigenic epigenetic alterations together with the development of inhibitors to target them promises to open the way toward personalized cancer treatment. Keywords: Bmi1, cancer, epigenetic reprogramming, epigenetic switching, Ezh2, histone deacetylase inhibitors, histone methyltransferase inhibitors, polycomb, stem cells, DNA mutations

Hematopoietic stem cells (HSCs) are defined by their exclusive capacity to both self-renew and to give rise to multipotent progenitors (MPPs) that in turn differentiate into the mature blood cell lineages. The tumor suppressor p53, in addition to its role in the regulation of the cell cycle, plays an importatn role in HSC self-renewal, although it has not fully resolved. Here we report that in super-p53 mice (sp53), which carry one extra gene dose of p53, the miR-33 is down-regulated in HSCs and highly expressed in MPPs. Transplantation assays of miR-33-transduced sp53 HSC results in a significant acquisition of repopulating capacity and a decrease of recipients survival. Moreover, high levels of miR-33 represses the endogenous level of p53 protein in murine embryonic fibroblasts (MEFs), leads both to neoplastic transformation and anchorage independent growth of MEFs, and displays a decrease of apoptotic response using tumor-derived cell lines. Accordingly, we demonstrate that miR-33-mediated down-regulation of p53 is dependent on the binding of miR-33 to two conserved motifs in the 3′UTR of p53. Together, these data show that the miR-33 modifies HSC repopulating efficiency of sp53 mice by impairing the p53 function. Defining the role of miR-33 in controlling the HSC self-renewal through p53 may lead to the prevention and treatment of hematopoietic disorders.