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Project description:KRAS drives lung cancer metastasis through lncRNA-mediated transcriptional and post-transcriptional regulation
| PRJNA512868 | ENA
Project description:Emerging evidence demonstrates that the DNA repair kinase DNA-PKcs exerts divergent roles in transcriptional regulation of unsolved consequence. Here, in vitro and in vivo interrogation demonstrate that DNA-PKcs functions as a selective modulator of transcriptional networks that induce cell migration, invasion, and metastasis. Accordingly, suppression of DNA-PKcs inhibits tumor metastases. Clinical assessment revealed that DNA-PKcs is significantly elevated in advanced disease and independently predicts for metastases, recurrence, and reduced overall survival. Further investigation demonstrated that DNA-PKcs in advanced tumors is highly activated, independent of DNA damage indicators. Combined, these findings reveal unexpected DNA-PKcs functions, identify DNA-PKcs as a potent driver of tumor progression and metastases, and nominate DNA-PKcs as a therapeutic target for advanced malignancies.
| S-EPMC4531387 | biostudies-literature
Project description:Lung adenocarcinoma (LUAD) is a fatal threat to human health, while the mechanism remains unclear, and the therapy brings limited therapeutic effects. Transcription factor Homeobox C11 (HOXC11) was previously proved to be related to hind limbs and metanephric development during the embryonic phase, and its role in tumors has been gradually recognized. Our study found that HOXC11 overexpressed in LUAD and was associated with worse overall survival. Moreover, its expression in lung cancer was regulated by IκB kinase α (IKKα), a pivotal kinase in NF-κB signaling, which was related to the ubiquitination of HOXC11. We further proved that HOXC11 could enhance the ability of proliferation, migration, invasion, colony formation, and the progression of the cell cycle in LUAD cells. Meanwhile, it also accelerated the formation of subcutaneous and lung metastases tumors. In contrast, loss of HOXC11 in LUAD cells significantly inhibited these malignant phenotypes. At the same time, HOXC11 regulated the expression of sphingosine kinase 1 (SPHK1) by directly binding to its promoter region. Therefore, we conclude that HOXC11 impacts the development of LUAD and facilitates lung cancer progression by promoting the expression of SPHK1.
| S-EPMC9950477 | biostudies-literature
Project description:BackgroundColorectal liver metastases (CRLM) continue to have a low survival rate. The number of CRLM regulators and clinical indicators remains limited. Long non-coding RNAs (lncRNAs) are a new master regulator of cell invasion and metastasis. However, the function and regulation mechanism of lncRNAs in colorectal cancer (CRC) metastasis are yet unknown.MethodsTo screen and identify CRLM-related lncRNAs, public transcriptome data were used. Gain and loss of function experiments were carried out to investigate the biological activities of lncRNA CRLM1 in vitro and in vivo. RNA sequencing (RNA-seq), chromatin isolation by RNA purification (ChIRP), immunofluorescence (IF), quantitative real-time PCR (qRT-PCR), western blotting, and rescue experiments were performed to explore the molecular mechanism of CRLM1. Moreover, identified the proteins, DNAs, and RNAs that interact with CRLM1.ResultsThe investigation of lncRNA expression dynamics in CRLM, primary CRC, and normal tissues in this work resulted in identifying a series of lncRNAs associated with metastasis, including CRLM1. CRLM1 inhibited apoptosis of CRC cells and promoted liver metastasis in Balb/C nude mice. CRLM1 was weakly associated with the chromatin regions of genes involved in cell adhesion and DNA damage, and this association was bidirectionally correlated with CRLM1-regulated pro-metastatic gene expression. CRLM1 physically interacts with the hnRNPK protein and promotes its nuclear localization. CRLM1 effectively enhances hnRNPK promoter occupancy and co-regulates the expression of a panel of metastatic genes.ConclusionsThe finding of the clinically significant lncRNA CRLM1 in promoting metastasis and regulating gene expression suggests a potential biomarker and target for CRLM therapy.
| S-EPMC9338583 | biostudies-literature
Project description:Multiple RNA-binding proteins and non-coding RNAs, such as microRNAs (miRNAs), are involved in post-transcriptional gene regulation through recognition motifs in the 3' untranslated region (UTR) of their target genes. The KRAS gene encodes a key signaling protein, and its messenger RNA (mRNA) contains an exceptionally long 3' UTR; this suggests that it may be subject to a highly complex set of regulatory processes. However, 3' UTR-dependent regulation of KRAS expression has not been explored in detail. Using extensive deletion and mutational analyses combined with luciferase reporter assays, we have identified inhibitory and stabilizing cis-acting regions within the KRAS 3' UTR that may interact with miRNAs and RNA-binding proteins, such as HuR. Particularly, we have identified an AU-rich 49-nt fragment in the KRAS 3' UTR that is required for KRAS 3' UTR reporter repression. This element contains a miR-185 complementary element, and we show that overexpression of miR-185 represses endogenous KRAS mRNA and protein in vitro. In addition, we have identified another 49-nt fragment that is required to promote KRAS 3' UTR reporter expression. These findings indicate that multiple cis-regulatory motifs in the 3' UTR of KRAS finely modulate its expression, and sequence alterations within a binding motif may disrupt the precise functions of trans-regulatory factors, potentially leading to aberrant KRAS expression.
| S-EPMC4914247 | biostudies-literature
Project description:Numerous studies have now demonstrated that lncRNAs can influence gene expression programs leading to cell and organismal phenotypes. Typically, lncRNA perturbations and concomitant changes in gene expression are measured on the timescale of many hours to days. Thus, we currently lack a temporally grounded understanding of the primary, secondary, and tertiary relationships of lncRNA-mediated transcriptional and epigenetic regulation-a prerequisite to elucidating lncRNA mechanisms. To begin to address when and where a lncRNA regulates gene expression, we genetically engineer cell lines to temporally induce the lncRNA Firre. Using this approach, we are able to monitor lncRNA transcriptional regulatory events from 15 min to four days. We observe that upon induction, Firre RNA regulates epigenetic and transcriptional states in trans within 30 min. These early regulatory events result in much larger transcriptional changes after 12 h, well before current studies monitor lncRNA regulation. Moreover, Firre-mediated gene expression changes are epigenetically remembered for days. Overall, this study suggests that lncRNAs can rapidly regulate gene expression by establishing persistent epigenetic and transcriptional states.
| S-EPMC11316132 | biostudies-literature
Project description:How the vast array of neuronal diversity is generated remains an unsolved problem. Here, we investigate how 29 morphologically distinct leg motoneurons are generated from a single stem cell in Drosophila. We identify 19 transcription factor (TF) codes expressed in immature motoneurons just before their morphological differentiation. Using genetic manipulations and a computational tool, we demonstrate that the TF codes are progressively established in immature motoneurons according to their birth order. Comparing RNA and protein expression patterns of multiple TFs reveals that post-transcriptional regulation plays an essential role in shaping these TF codes. Two RNA-binding proteins, Imp and Syp, expressed in opposing gradients in immature motoneurons, control the translation of multiple TFs. The varying sensitivity of TF mRNAs to the opposing gradients of Imp and Syp in immature motoneurons decrypts these gradients into distinct TF codes, establishing the connectome between motoneuron axons and their target muscles.
| S-EPMC9479746 | biostudies-literature
Project description:BACKGROUND/AIMS:Schlafen12 (SLFN12) promotes human intestinal and prostatic epithelial differentiation. We sought to determine whether SLFN12 reduces triple-negative breast cancer (TNBC) aggressiveness. METHODS:We validated bioinformatics analyses of publicly available databases by staining human TNBC. After virally overexpressing or siRNA-reducing SLFN12 in TNBC cell lines, we measured proliferation by CCK-8 assay, invasion into basement-membrane-coated pores, mRNA by q-RT-PCR and protein by Western blotting. Flow cytometry assessed proliferation and stem cell marker expression, and sorted CD44+/CD24- cells. Stemness was also assessed by mammosphere formation, and translation by click-it-AHA chemistry. RESULTS:SLFN12 expression was lower in TNBC tumors and correlated with survival. SLFN12 overexpression reduced TNBC MDA-MB-231, BT549, and Hs578T proliferation. In MDA-MB-231 cells, AdSLFN12 reduced invasion, promoted cell cycle arrest, increased E-cadherin promoter activity, mRNA, and protein, and reduced vimentin expression and protein. SLFN12 knockdown increased vimentin. AdSLFN12 reduced the proportion of MDA-MB-231 CD44+CD24- cells, with parallel differentiation changes. SLFN12 overexpression reduced MDA-MB-231 mammosphere formation. SLFN12 overexpression decreased ZEB1 and Slug protein despite increased ZEB1 and Slug mRNA in all three lines. SLFN12 overexpression accelerated MDA-MB-231 ZEB1 proteasomal degradation and slowed ZEB1 translation. SLFN12 knockdown increased ZEB1 protein. Coexpressing ZEB1 attenuated the SLFN12 effect on E-cadherin mRNA and proliferation in all three lines. CONCLUSION:SLFN12 may reduce TNBC aggressiveness and improve survival in part by a post-transcriptional decrease in ZEB1 that promotes TNBC cancer stem cell differentiation.
| S-EPMC7007982 | biostudies-literature
Project description:Understanding the mechanisms of androgen receptor (AR) activation in the milieu of low androgen is critical to effective treatment of castration-resistant prostate cancer (CRPC). Here, we report HOTAIR as an androgen-repressed lncRNA, and, as such, it is markedly upregulated following androgen deprivation therapies and in CRPC. We further demonstrate a distinct mode of lncRNA-mediated gene regulation, wherein HOTAIR binds to the AR protein to block its interaction with the E3 ubiquitin ligase MDM2, thereby preventing AR ubiquitination and protein degradation. Consequently, HOTAIR expression is sufficient to induce androgen-independent AR activation and drive the AR-mediated transcriptional program in the absence of androgen. Functionally, HOTAIR overexpression increases, whereas HOTAIR knockdown decreases, prostate cancer cell growth and invasion. Taken together, our results provide compelling evidence of lncRNAs as drivers of androgen-independent AR activity and CRPC progression, and they support the potential of lncRNAs as therapeutic targets.
| S-EPMC4757469 | biostudies-literature
Project description:The immune-suppressive tumor microenvironment promotes metastatic spread and outgrowth. One of the major contributors is tumor-associated myeloid cells. However, the molecular mechanisms regulating their differentiation and function are not well understood. Here we report lamin A/C, a nuclear lamina protein associated with chromatin remodeling, was one of the critical regulators in cellular reprogramming of tumor-associated myeloid cells. Using myeloid-specific lamin A/C knockout mice and triple-negative breast cancer (TNBC) mouse models, we discovered that the loss of lamin A/C drives CD11b+ Ly6G+ granulocytic lineage differentiation, alters the production of inflammatory chemokines, decreases host antitumor immunity, and increases metastasis. The underlying mechanisms involve an increased H3K4me3 leading to the upregulation of transcription factors (TFs) Gfi-1 and C/EBPε. Decreased lamin A/C and increased Gfi-1 and C/EBPε were also found in the granulocytic subset in the peripheral blood of human cancer patients. Our data provide a mechanistic understanding of myeloid lineage differentiation and function in the immune-suppressive microenvironment in TNBC metastasis.
| S-EPMC7282947 | biostudies-literature