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The role of lncRNAs in the pathogenesis of cancer, including colorectal cancer (CRC), has repeatedly been demonstrated. However, very few lncRNAs have been well annotated functionally. Our study identified a novel lncRNA upregulated in CRC, NONHSAT136151, which was correlated with clinical progression. In functional assays, NONHSAT136151 significantly enhanced CRC cell proliferation, migration and invasion. Mechanistically, NONHSAT136151 interacted with RNA‐binding protein (RBP) QKI (Quaking) to interfere with QKI binding to target mRNAs and regulate their expression. As well, FOXP3 may be causally related to the dysregulation of NONHSAT136151 in CRC cells through its transcriptional activity. In conclusion, our findings identified a novel lncRNA regulated by FOXP3 participates in CRC progression through interacting with QKI, indicating a novel lncRNA‐RBP interaction mechanism is involved in CRC pathogenesis. [ABSTRACT FROM AUTHOR]

Quaking homolog (QKI) is a member of the RNA‐binding signal transduction and activator of proteins family. Previous studies showed that QKI possesses the tumour suppressor activity in human cancers by interacting with the 3'‐untraslated region (3'‐UTR) of various gene transcripts via the STAR domain. This study first assessed the association of QKI‐6 expression with clinicopathological and survival data from bladder cancer patients and then investigated the underlying molecular mechanisms. Bladder cancer tissues (n = 223) were subjected to immunohistochemistry, and tumour cell lines and nude mice were used for different in vitro and in vivo assays following QKI‐6 overexpression or knockdown. QKI‐6 down‐regulation was associated with advanced tumour TNM stages and poor patient overall survival. QKI‐6 overexpression inhibited bladder cancer cell growth and invasion capacity, but induced tumour cell apoptosis and cell cycle arrest. Furthermore, ectopic expression of QKI‐6 reduced tumour xenograft growth and expression of proliferation markers, Ki67 and PCNA. However, knockdown of QKI‐6 expression had opposite effects in vitro and in vivo. QKI‐6 inhibited expression of E2 transcription factor 3 (E2F3) by directly binding to the E2F3 3'‐UTR, whereas E2F3 induced QKI‐6 transcription by binding to the QKI‐6 promoter in negative feedback mechanism. QKI‐6 expression also suppressed activity and expression of nuclear factor‐κB (NF‐κB) signalling proteins in vitro, implying a novel multilevel regulatory network downstream of QKI‐6. In conclusion, QKI‐6 down‐regulation contributes to bladder cancer development and progression. [ABSTRACT FROM AUTHOR]

The microRNA‐200 (miR‐200) family plays a major role in specifying epithelial phenotype by preventing expression of the transcription repressors ZEB1 and ZEB2, which are well‐known regulators of the epithelial‐to‐mesenchymal transition (EMT) in epithelial tumors including oral squamous cell carcinoma (OSCC). Here, we elucidated whether miR‐200 family members control RNA‐binding protein quaking (QKI), a newly identified tumor suppressor that is regulated during EMT. We predicted that miR‐200a and miR‐200b could recognize QKI 3′‐UTR by analyzing TargetScan and The Cancer Genome Atlas head and neck squamous cell carcinoma (HNSCC) dataset. Forced expression of miR‐200b/a/429 inhibited expression of ZEB1/2 and decreased cell migration in OSCC cell lines CAL27 and HSC3. QKI expression was also suppressed by miR‐200 overexpression, and the 3′‐UTR of QKI mRNA was directly targeted by miR‐200 in luciferase reporter assays. Interestingly, shRNA‐mediated knockdown of QKI led to pronounced EMT and protumor effects in both in vitro and in vivo studies of OSCC. Furthermore, high expression of QKI protein is associated with favorable prognosis in surgically resected HNSCC and lung adenocarcinoma. In conclusion, QKI increases during EMT and is targeted by miR‐200; while, it suppresses EMT and tumorigenesis. We suggest that QKI and miR‐200 form a negative feedback loop to maintain homeostatic responses to EMT‐inducing signals. What's new? The epithelial‐mesenchymal transition is controlled by various transcription factors and non‐coding RNAs. The miR‐200 family of microRNAs inhibit the EMT by targeting certain transcription factors. In this study, the authors identified the gene QKI as a novel target of miR‐200 in oral and lung cancer cells. These microRNAs suppressed QKI expression, and QKI knockdown reduced miR‐200 expression, suggesting the two interact in a negative feedback loop. QKI knockdown also promoted cell growth, EMT, and invasion. On the other hand, microarray data from surgical samples showed that high QKI expression correlated with good outcomes for patients with HSNCC and lung cancer. [ABSTRACT FROM AUTHOR]

Increasing interest has been devoted in recent years to the understanding of alternative splicing in cancer. In this study, we performed a genome-wide analysis to identify cancer-associated splice variants in non-small cell lung cancer. We discovered and validated novel differences in the splicing of genes known to be relevant to lung cancer biology, such as NFIB, ENAH or SPAG9. Gene enrichment analyses revealed an important contribution of alternative splicing to cancer-related molecular functions, especially those involved in cytoskeletal dynamics. Interestingly, a substantial fraction of the altered genes found in our analysis were targets of the protein quaking (QKI), pointing to this factor as one of the most relevant regulators of alternative splicing in non-small cell lung cancer. We also found that ESYT2, one of the QKI targets, is involved in cytoskeletal organization. ESYT2-short variant inhibition in lung cancer cells resulted in a cortical distribution of actin whereas inhibition of the long variant caused an increase of endocytosis, suggesting that the cancer-associated splicing pattern of ESYT2 has a profound impact in the biology of cancer cells. Finally, we show that low nuclear QKI expression in non-small cell lung cancer is an independent prognostic factor for disease-free survival (HR = 2.47; 95% CI = 1.11–5.46, P = 0.026). In conclusion, we identified several splicing variants with functional relevance in lung cancer largely regulated by the splicing factor QKI, a tumor suppressor associated with prognosis in lung cancer. [ABSTRACT FROM AUTHOR]

Flight speed is a predictive indicator of cattle temperament and is associated with feed efficiency phenotypes. Genetic markers associated with both traits may assist with selection of calmer animals with improved economic value. A preliminary genome-wide association study determined chromosomal regions on BTA9, and 17 were associated with flight speed. The genes quaking ( QKI), glutamate receptor, ionotropic, AMPA 2 ( GRIA2) and glycine receptor β ( GLRB) were identified in these regions as potential functional candidates. Beef steers ( n = 1057) were genotyped with SNPs located within and flanking these genes. One SNP located near QKI and one near GRIA2 were nominally associated with flight speed ( P ≤ 0.05) although neither was significant after Bonferroni correction. Several studies have shown a correlation between flight speed and feed intake or gain; therefore, we also analyzed SNPs on BTA6:38-39 Mb known to be associated with average daily gain ( ADG) and average daily feed intake ( ADFI) for association with flight speed. Several SNPs on BTA6 were associated with flight speed ( P ≤ 0.005), and three were significant after Bonferroni correction. These results suggest that the genes tested are unlikely to contribute to flight speed variation for our cattle population, but SNPs on BTA6 associated with ADG and ADFI may influence temperament. Use of these markers to select for economically important feed efficiency phenotypes may produce cattle with more desirable temperaments. [ABSTRACT FROM AUTHOR]

Adipose tissue controls numerous physiological processes, and its dysfunction has a causative role in the development of systemic metabolic disorders. The role of posttranscriptional regulation in adipose metabolism has yet to be fully understood. Here, we show that the RNA‐binding protein quaking (QKI) plays an important role in controlling metabolic homeostasis of the adipose tissue. QKI‐deficient mice are resistant to high‐fat‐diet (HFD)‐induced obesity. Additionally, QKI depletion increased brown fat energy dissipation and browning of subcutaneous white fat. Adipose tissue‐specific depletion of QKI in mice enhances cold‐induced thermogenesis, thereby preventing hypothermia in response to cold stimulus. Further mechanistic analysis reveals that QKI is transcriptionally induced by the cAMP‐cAMP response element‐binding protein (CREB) axis and restricts adipose tissue energy consumption by decreasing stability, nuclear export, and translation of mRNAs encoding UCP1 and PGC1α. These findings extend our knowledge of the significance of posttranscriptional regulation in adipose metabolic homeostasis and provide a potential therapeutic target to defend against obesity and its related metabolic diseases. Synopsis: RNA binding protein QKI is induced by cold stimulus and impedes thermogenesis by repressing translation of thermogenesis regulators such as UCP1 and PGC1α. QKI deficient mice are protected from high fat diet induced obesity and insulin resistance.QKI deficiency promotes adipose thermogenesis and prevents cold induced hypothermia.QKI binds mRNAs encoding UCP1 and PGC1α and decreases their stability, nuclear export and translational efficiency.cAMP/CREB signaling transcriptionally upregulates QKI, which in turn represses thermogenesis. [ABSTRACT FROM AUTHOR]