Please use this identifier to cite or link to this item: https://doi.org/10.1186/s13073-017-0511-4
Title: Linking FOXO3, NCOA3, and TCF7L2 to Ras pathway phenotypes through a genomewide forward genetic screen in human colorectal cancer cells
Authors: Kundu, S
Ali, M.A
Handin, N
Padhan, N
Larsson, J
Karoutsou, M
Ban, K 
Wisniewski, J.R
Artursson, P
He, L
Hellström, M
Sjöblom, T
Keywords: cetuximab
epidermal growth factor receptor
glucose
glucose transporter 1
mitogen activated protein kinase
mitogen activated protein kinase kinase
Ras protein
transcription factor 7 like 2
transcription factor FKHRL1
cetuximab
FOXO3 protein, human
glucose transporter 1
mitogen activated protein kinase
NCOA3 protein, human
Ras protein
SLC2A1 protein, human
small interfering RNA
steroid receptor coactivator 3
TCF7L2 protein, human
transcription factor 7 like 2
transcription factor FKHRL1
anchorage independent growth
Article
cancer growth
colorectal cancer cell line
controlled study
drug sensitivity
enzyme phosphorylation
FOXO3 gene
gene
gene expression
gene knockdown
gene sequence
genetic screening
GLUT1 gene
mutagenesis
NCOA3 gene
oncogene K ras
phenotype
priority journal
TCF7L2 gene
transposon
wild type
cell proliferation
colorectal tumor
drug effect
drug resistance
gene expression regulation
genetic screening
genetics
human
human genome
metabolism
pathology
phenotype
phosphorylation
proteomics
signal transduction
tumor cell line
Cell Line, Tumor
Cell Proliferation
Cetuximab
Colorectal Neoplasms
DNA Transposable Elements
Drug Resistance, Neoplasm
Extracellular Signal-Regulated MAP Kinases
Forkhead Box Protein O3
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Genetic Testing
Genome, Human
Glucose Transporter Type 1
Humans
Nuclear Receptor Coactivator 3
Phenotype
Phosphorylation
Proteomics
ras Proteins
RNA, Small Interfering
Signal Transduction
Transcription Factor 7-Like 2 Protein
Issue Date: 2018
Citation: Kundu, S, Ali, M.A, Handin, N, Padhan, N, Larsson, J, Karoutsou, M, Ban, K, Wisniewski, J.R, Artursson, P, He, L, Hellström, M, Sjöblom, T (2018). Linking FOXO3, NCOA3, and TCF7L2 to Ras pathway phenotypes through a genomewide forward genetic screen in human colorectal cancer cells. Genome Medicine 10 (1) : 2. ScholarBank@NUS Repository. https://doi.org/10.1186/s13073-017-0511-4
Rights: Attribution 4.0 International
Abstract: Background: The Ras pathway genes KRAS, BRAF, or ERBBs have somatic mutations in ~ 60% of human colorectal carcinomas. At present, it is unknown whether the remaining cases lack mutations activating the Ras pathway or whether they have acquired mutations in genes hitherto unknown to belong to the pathway. Methods: To address the second possibility and extend the compendium of Ras pathway genes, we used genomewide transposon mutagenesis of two human colorectal cancer cell systems deprived of their activating KRAS or BRAF allele to identify genes enabling growth in low glucose, a Ras pathway phenotype, when targeted. Results: Of the 163 recurrently targeted genes in the two different genetic backgrounds, one-third were known cancer genes and one-fifth had links to the EGFR/Ras/MAPK pathway. When compared to cancer genome sequencing datasets, nine genes also mutated in human colorectal cancers were identified. Among these, stable knockdown of FOXO3, NCOA3, and TCF7L2 restored growth in low glucose but reduced MEK/MAPK phosphorylation, reduced anchorage-independent growth, and modulated expressions of GLUT1 and Ras pathway related proteins. Knockdown of NCOA3 and FOXO3 significantly decreased the sensitivity to cetuximab of KRAS mutant but not wild-type cells. Conclusions: This work establishes a proof-of-concept that human cell-based genome-wide forward genetic screens can assign genes to pathways with clinical importance in human colorectal cancer. © The Author(s). 2018.
Source Title: Genome Medicine
URI: https://scholarbank.nus.edu.sg/handle/10635/178120
ISSN: 1756994X
DOI: 10.1186/s13073-017-0511-4
Rights: Attribution 4.0 International
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