Effect of depletion of KLF9 on gene expression of small cell lung cancer cells in vitro
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE299679 | GEO | 2025/06/16
REPOSITORIES: GEO
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Project description:Small-cell lung cancer (SCLC) arises from neuroendocrine cells within the lung. Along with deletion or loss of function Rb and TP53 mutations, which occur in almost all cases, subsets of SCLC are driven by specific transcription factors including ASCL1, NEUROD1, POU2F3, or YAP1. Various MYC family members provide further inter-tumor heterogeneity. Despite this heterogeneity in SCLC, current treatment for SCLC is subtype agnostic. Although most patients are initially responsive to first line etoposide and platin chemotherapy they soon develop resistance with no effective second line therapy. A recent large NCI screen showed that over 60 SCLC cell line models responded to 500+ investigational drugs in a manner highly correlated with etoposide responses, suggesting none of these drugs would provide benefit for SCLC therapy beyond current chemotherapy. By analyzing publicly available data of shRNA and CRISPR screens in addition to our own RNA-seq expression data we identified KDM4A as a potential candidate to target in SCLC. To underscore the potential of KDM4A as an anti-SCLC target, we tested chemotherapy drug and three JmjC KDM inhibitors across a panel of SCLC cell lines representing all the SCLC transcription factor subtypes and found that SCLC responses to JmjC KDM inhibitors do not correlate to their responses to chemotherapy. Furthermore, we found upon treatment with pan-JmjC KDM inhibitor, JIB-04, many genes in the ER stress signaling pathways are upregulated in SCLC lines, suggesting this is the mechanistic path leading to SCLC slower growth or death. Additionally, analysis found that JIB-04 resistant cells activate pro-survival pathways such as mTOR to perhaps overcome the effects of JIB-04 treatment. Furthermore, the loss of KDM4A in SCLC cell line led to slower proliferation and activity in the ER stress signaling pathway.
2024-10-10 | GSE208446 | GEO
Project description:Kruppel-like factor 9 (Klf9), a zinc-finger transcription factor, is implicated in the control of cell proliferation, cell differentiation and cell fate in brain and uterus. Using Klf9 null mutant mice, we have investigated the involvement of Klf9 in small intestine crypt-villus cell renewal and lineage determination. We report the predominant expression of Klf9 gene in small intestine smooth muscle (muscularis externa). Jejunums null for Klf9 have shorter villi, reduced crypt stem/transit cell proliferation, and altered lineage determination as indicated by decreased and increased numbers of Goblet and Paneth cells, respectively. A stimulatory role for Klf9 in villus cell migration was demonstrated by BrdU labeling. Results suggest that Klf9 controls the elaboration, from small intestine smooth muscle, of molecular mediator(s) of crypt cell proliferation and lineage determination, and of villus cell migration. Experiment Overall Design: Total RNA was extracted in parallel from the jejunums of five WT and five Klf9-/- male mice (PND 30) using TRIzol reagent (Invitrogen, Carlsbad, CA). Conversion of each RNA preparation to corresponding fragmented cRNA. Fifteen ug of each cRNA was hybridized for 16 hours to an Affymetrix mouse 430A GeneChip. Ten GeneChips (each corresponding to a single animal) were hybridized, washed and scanned in parallel. Following the wash, signal amplification, and signal detection steps, GeneChips were scanned (Agilent GeneArray laser scanner) and the resultant images quantified using Affymetrix MAS 5.0 software.
2007-11-15 | E-GEOD-6443 | biostudies-arrayexpress
Project description:Effect of depletion of KLF9 on gene expression of small cell lung cancer cells in vitro
| PRJNA1275993 | ENA
Project description:To determine miRNAs regulated by TTF-1 in SCLC cell lines, miRNA array analyses were carried out in NCI-H209 cells following TTF-1 knockdown
2018-07-10 | GSE106164 | GEO
Project description:Mitochondrial dynamics and mitophagy are intimately linked physiological processes that are essential for cardiac homeostasis. Here we show that cardiac Klf9 is dysregulated in human and rodent cardiomyopathy. Young adult global Klf9-knockout mice displayed hypertrophic cardiomyopathy that was characterized by depressed systolic function, increased left ventricular mass and pulmonary congestion. Klf9 knockout led to mitochondrial disarray and fragmentation in cardiomyocytes. Biochemical analysis confirmed that mitochondrial respiratory function was impaired in Klf9-knockout cardiomyocytes, with reduced myocardial ATP levels and elevated ROS. Furthermore, cardiac-specific Klf9-deficient mice phenocopied global Klf9-knockout mice, suggesting that cardiac Klf9 is essential for mitochondrial homeostasis and heart function. Moreover, cardiac Klf9 deficiency inhibited mitophagy induced by angiotensin II (ANGII), thereby leading to accumulation of dysfunctional mitochondria and acceleration of heart failure in mice in response to ANGII treatment. In contrast, cardiac-specific Klf9 transgene improved cardiac systolic function via promoting mitophagy in mice in response to ANGII treatment. Molecular mechanism studies indicated that Klf9 knockout decreased the expression of PGC-1α and its target genes involved in mitochondrial energy metabolism. Moreover, Klf9 controlled the expression of Mfn2 by directly binding to its promoter region, thereby regulating mitochondrial dynamics and mitophagy. Finally, we performed Mfn2 rescue experiments in Klf9-CKO mice and found that AAV-mediated Mfn2 rescue in heart improved cardiac mitochondrial and systolic function in Klf9-CKO mice treated with or without ANGII. Thus, Klf9 integrates cardiac energy metabolism, mitochondrial dynamics and mitophagy. Modulating Klf9 activity may have therapeutic potential in the treatment of heart failure.
2024-10-03 | GSE278326 | GEO
Project description:To identify putative target genes of the transcription factor Klf9 in primary keratinocytes we over-expressed Klf9 in these cells using a lentiviral delivery system. We detected several hundred genes that show differential expression levels following ectopic Klf9 expression including several genes that are involved in proliferation and cell cycle control. These results allow insights into the mechanisms by which Klf9 regulates proliferation in primary keratinocytes. Primary human neonatal foreskin keratinocytes were infected with equal viral titers of a GFP and KLF9 expression construct, respectively. Cells were harvested 2,4 and 7 days after infection and total RNA was used to perform whole genome microarray analysis.
2012-07-30 | E-GEOD-36014 | biostudies-arrayexpress
Project description:Characterization of 63 small cell lung cancer (SCLC) cell lines and a comparator set of non-small cell lung cancer and normal counterpart cells, including drug sensitivity testing, gene expression profiling and microRNA expression profiling have been completed. Data and tools for searching these data will be made publicly available through the NCI Developmental Therapeutics Program at http://SCLC.cancer.gov. SCLC is an aggressive, recalcitrant cancer and have seen limited treatment advances in the last 30 years. Drug sensitivity data coupled with the transcription and microRNA profiles of a cohort of SCLC cell lines may help define novel treatment paradigms.
2016-05-01 | GSE73160 | GEO
Project description:To identify putative target genes of the transcription factor Klf9 in primary keratinocytes we over-expressed Klf9 in these cells using a lentiviral delivery system. We detected several hundred genes that show differential expression levels following ectopic Klf9 expression including several genes that are involved in proliferation and cell cycle control. These results allow insights into the mechanisms by which Klf9 regulates proliferation in primary keratinocytes.
2012-07-31 | GSE36014 | GEO
Project description:Krueppel-like factor 9 (Klf9) is a DNA-binding transcription factor that has been implicated in neuronal development and regeneration. We used mouse hippocampus-derived HT22 cell line to identify genes differentially regulated by forced Klf9 expression. We stably transfected HT22 cells with pCDNA6:TR (encoding the Tet repressor) and pCDNA6:TO-Klf9 (encoding Klf9 downstream of the Tet operator), allowing doxycycline(dox)-inducible expression of Klf9. We chose a stably transfected clone with baseline Klf9 mRNA level similar to that of untransfected HT22 cells (parent line) and approximately 10-fold induction after dox treatment. We conducted RNA-seq on stably transfected HT22 cells treated with or without dox for 8 hours; we also conducted RNA-seq on parent cells subjected to the same dox treatment to separate nonspecific effects of dox from the effects of forced Klf9 expression. Analysis of RNA-seq data found 217 gene repressed and 21 upregulated by forced Klf9 expression (FDR-adjusted p<.005; because fold changes were small we used a stringent p value cutoff to ensure that we were studying genes likely to be bona fide targets), showing that Klf9 functions primarily as a transcriptional repressor. Gene ontology analysis showed that Klf9-repressed genes were enriched in cytoskeletal and Wnt signaling-related genes.
2019-09-19 | GSE87093 | GEO
Project description:PTK7 was identified from a meta-analysis of 1905 non-small-cell lung cancer (NSCLC) samples across 12 datasets to be one of seven genes commonly up-regulated in lung adenocarcinoma (ADC). Using ADC cell lines NCI-H1299 and NCI-H2009, disruption of PTK7 resulted in decreased cell viability and induction of apoptosis. A xenotransplantation model of the cell lines with PTK7 knock-down also resulted in decreased tumor burden. We assayed gene expression in these cell lines after PTK7 knock-down by shRNA to uncover deregulated pathways and genes. 8 samples were analyzed. In each cell line, we knocked down PTK7 with 2 independent hairpins, and 2 control hairpins targeting luciferase and GFP. Thus, NCI-H1299 has 2 samples of PTK7 knock-down, and 2 samples of control knock down. NCI-H2009 has similar samples.
2014-01-01 | E-GEOD-50138 | biostudies-arrayexpress