KRAS inhibition impacts chromatin organization and transcriptional performance in colorectal cancer cells [HCT116 RNA-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1051274 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27183600_1.fastq.gz | Fastqsanger.gz | |||
| SRR27183600_2.fastq.gz | Fastqsanger.gz | |||
| SRR27183601_1.fastq.gz | Fastqsanger.gz | |||
| SRR27183601_2.fastq.gz | Fastqsanger.gz | |||
| SRR27183602_1.fastq.gz | Fastqsanger.gz |
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Project description:KRAS inhibition impacts chromatin organization and transcriptional performance in colorectal cancer cells
| PRJNA1052048 | ENA
Project description:Preclinical and clinical data revealed that targeting KRAS mutant tumors is more challenging than expected. While initially sensitive to the treatment, cancer cells have the capability to rapidly bypass dependence on this oncogene to acquire a drug-tolerant phenotype. Gaining a comprehensive understanding of the mechanisms underlying the transition from a drug-sensitive to a drug-tolerant state holds the key to invaluable insights. Such insights will inform the development of therapeutic strategies aimed at disrupting intrinsic or adaptive resilience, ultimately enhancing therapeutic outcomes. Building upon this rationale, we established three-dimensional culture models of mutant KRAS CRC cell lines with distinct KRAS dependencies to investigate the cellular response to KRAS silencing. Our approach revealed a unique response in KRAS-dependent cells, characterized by G0/G1 cell cycle arrest and entry into a quiescent-like state. Proteomics analysis identified nucleosome assembly, regulation of gene expression, mRNA splicing, and mRNA processing as the top biologic processes specifically up-regulated in KRAS-dependent CRC cell lines upon KRAS silencing. Additionally, alterations in histone 3 post-translational modifications and chromatin compaction were also observed, along with enhanced transcriptional performance revealed by longitudinal RNA-Seq analysis. Our discoveries substantiate the existence of an epigenetic mechanism responsible for inducing tolerance to KRAS loss. This mechanism relies on both chromatin reorganization and transcriptional upregulation, illuminating the cancer cells' remarkable capacity to swiftly adapt, survive, and sustain malignancy even in the absence of oncogenic KRAS.
2023-12-15 | GSE249954 | GEO
Project description:KRAS inhibition impacts chromatin organization and transcriptional performance in colorectal cancer cells [LS174T RNA-seq]
| PRJNA1052057 | ENA
Project description:KRAS inhibition impacts chromatin organization and transcriptional performance in colorectal cancer cells [SW480 RNA-seq]
| PRJNA1052056 | ENA
Project description:Preclinical and clinical data revealed that targeting KRAS mutant tumors is more challenging than expected. While initially sensitive to the treatment, cancer cells have the capability to rapidly bypass dependence on this oncogene to acquire a drug-tolerant phenotype. Gaining a comprehensive understanding of the mechanisms underlying the transition from a drug-sensitive to a drug-tolerant state holds the key to invaluable insights. Such insights will inform the development of therapeutic strategies aimed at disrupting intrinsic or adaptive resilience, ultimately enhancing therapeutic outcomes. Building upon this rationale, we established three-dimensional culture models of mutant KRAS CRC cell lines with distinct KRAS dependencies to investigate the cellular response to KRAS silencing. Our approach revealed a unique response in KRAS-dependent cells, characterized by G0/G1 cell cycle arrest and entry into a quiescent-like state. Proteomics analysis identified nucleosome assembly, regulation of gene expression, mRNA splicing, and mRNA processing as the top biologic processes specifically up-regulated in KRAS-dependent CRC cell lines upon KRAS silencing. Additionally, alterations in histone 3 post-translational modifications and chromatin compaction were also observed, along with enhanced transcriptional performance revealed by longitudinal RNA-Seq analysis. Our discoveries substantiate the existence of an epigenetic mechanism responsible for inducing tolerance to KRAS loss. This mechanism relies on both chromatin reorganization and transcriptional upregulation, illuminating the cancer cells' remarkable capacity to swiftly adapt, survive, and sustain malignancy even in the absence of oncogenic KRAS.
2023-12-15 | GSE250117 | GEO
Project description:Preclinical and clinical data revealed that targeting KRAS mutant tumors is more challenging than expected. While initially sensitive to the treatment, cancer cells have the capability to rapidly bypass dependence on this oncogene to acquire a drug-tolerant phenotype. Gaining a comprehensive understanding of the mechanisms underlying the transition from a drug-sensitive to a drug-tolerant state holds the key to invaluable insights. Such insights will inform the development of therapeutic strategies aimed at disrupting intrinsic or adaptive resilience, ultimately enhancing therapeutic outcomes. Building upon this rationale, we established three-dimensional culture models of mutant KRAS CRC cell lines with distinct KRAS dependencies to investigate the cellular response to KRAS silencing. Our approach revealed a unique response in KRAS-dependent cells, characterized by G0/G1 cell cycle arrest and entry into a quiescent-like state. Proteomics analysis identified nucleosome assembly, regulation of gene expression, mRNA splicing, and mRNA processing as the top biologic processes specifically up-regulated in KRAS-dependent CRC cell lines upon KRAS silencing. Additionally, alterations in histone 3 post-translational modifications and chromatin compaction were also observed, along with enhanced transcriptional performance revealed by longitudinal RNA-Seq analysis. Our discoveries substantiate the existence of an epigenetic mechanism responsible for inducing tolerance to KRAS loss. This mechanism relies on both chromatin reorganization and transcriptional upregulation, illuminating the cancer cells' remarkable capacity to swiftly adapt, survive, and sustain malignancy even in the absence of oncogenic KRAS.
2023-12-15 | GSE250118 | GEO
Project description:Cancer cells that express oncogenic alleles of RAS typically require sustained expression of the mutant allele for survival, but the molecular basis of this oncogene dependency remains incompletely understood. To identify genes that can functionally substitute for oncogenic RAS, we systematically expressed 15,294 open reading frames in a human KRAS-dependent colon cancer cell line engineered to express an inducible KRAS-specific shRNA. We found 147 genes that promoted survival in the setting of KRAS suppression. In this model, the transcriptional co-activator YAP1 rescued cell viability in KRAS-dependent cells upon suppression of KRAS and was required for KRAS-induced cell transformation. Acquired resistance to Kras suppression in a Kras-driven murine lung cancer model also involved increased YAP1 signaling. KRAS and YAP1 converge on the transcription factor FOS and activate a transcriptional program involved in regulating the epithelial-mesenchymal transition (EMT). Together, these findings implicate transcriptional regulation of EMT by YAP1 as a significant component of oncogenic RAS signaling. We used microarrays to compare gene expression in HCT116 cells in which we suppressed KRAS expression doxycycline-inducible shRNA targeting KRAS compared to cells treated with media alone (no shKRAS induced). We express KRAS, LacZ, and YAP1 in each condition to identify genes transcriptionally involved in the rescue of KRAS suppression. HCT116 cells harboring doxycycline-inducible shKRAS (HCTtetK) expressing either LacZ, KRAS, or YAP1, were treated with doxycycline for 30 hours to suppress KRAS. Untreated (no doxycycline) cells expressing each ORF were used as control. Total RNA was collected using PerfectPure RNA Cultured Cell Kit (5Prime) and expression profiling was performed on Human Genome U133A 2.0 Array (Affymetrix) using the Dana Farber Cancer Institute Microarray Core.
2014-07-22 | E-GEOD-55942 | biostudies-arrayexpress
Project description:RNA-seq of HCT116 KRAS G13D and HCT116 KRAS WT cell lines with control or CFIm25 knockdown
| PRJEB38811 | ENA
Project description:Cancer cells that express oncogenic alleles of RAS typically require sustained expression of the mutant allele for survival, but the molecular basis of this oncogene dependency remains incompletely understood. To identify genes that can functionally substitute for oncogenic RAS, we systematically expressed 15,294 open reading frames in a human KRAS-dependent colon cancer cell line engineered to express an inducible KRAS-specific shRNA. We found 147 genes that promoted survival in the setting of KRAS suppression. In this model, the transcriptional co-activator YAP1 rescued cell viability in KRAS-dependent cells upon suppression of KRAS and was required for KRAS-induced cell transformation. Acquired resistance to Kras suppression in a Kras-driven murine lung cancer model also involved increased YAP1 signaling. KRAS and YAP1 converge on the transcription factor FOS and activate a transcriptional program involved in regulating the epithelial-mesenchymal transition (EMT). Together, these findings implicate transcriptional regulation of EMT by YAP1 as a significant component of oncogenic RAS signaling. We used microarrays to compare gene expression in HCT116 cells in which we suppressed KRAS expression doxycycline-inducible shRNA targeting KRAS compared to cells treated with media alone (no shKRAS induced). We express KRAS, LacZ, and YAP1 in each condition to identify genes transcriptionally involved in the rescue of KRAS suppression.
2014-07-22 | GSE55942 | GEO
Project description:Colorectal cancer (CRC) responses to mutant-selective KRAS inhibitors remain modest, with stable disease and rapid recurrence as the most common outcomes. The molecular mechanisms enabling CRC cells to tolerate KRAS inhibition and ultimately develop resistance remain poorly understood. Here, we investigated early transcriptional and proteomic responses to KRAS silencing in 3D CRC cell line spheroid models, aiming to identify pathways associated with sensitivity or resistance to KRAS blockade. Cell lines were stratified into KRAS silencing-sensitive (HCT116 and SW480) and -resistant (LS174T and SW837) groups based on spheroid growth, cell cycle progression, and apoptosis induction. Transcriptional profiling revealed the unfolded protein response (UPR) and WNT/β-catenin signaling as pathways specifically upregulated in KRAS silencing-sensitive cells and downregulated in resistant cells. Proteomic analysis of membrane-enriched fractions further supported UPR deregulation, showing a pronounced downregulation of translation-related proteins in sensitive cells. Functional assays validated that the sensitive cell line HCT116 exhibits reduced protein aggregation and lower translational capacity upon KRAS knockdown, consistent with UPR activation. Pharmacological inhibition of IRE1α-mediated UPR signaling did not revert KRAS silencing-induced cell cycle arrest or apoptosis in this cell line. Collectively, our results highlight the UPR activation as an early adaptive response of KRAS-dependent CRC cells tolerant to KRAS silencing.
2024-02-06 | GSE254832 | GEO