An in vivo functional genomics screen of nuclear receptors and their co-regulators identifies FOXA1 as an essential gene in lung tumorigenesis.

Neoplasia : an International Journal for Oncology Research
Suzie K HightJohn D Minna

Abstract

Using a mini-library of 1062 lentiviral shRNAs targeting 40 nuclear hormone receptors and 70 of their co-regulators, we searched for potential therapeutic targets that would be important during in vivo tumor growth using a parallel in vitro and in vivo shRNA screening strategy in the non-small cell lung cancer (NSCLC) line NCI-H1819. We identified 21 genes essential for in vitro growth, and nine genes specifically required for tumor survival in vivo, but not in vitro: NCOR2, FOXA1, HDAC1, RXRA, RORB, RARB, MTA2, ETV4, and NR1H2. We focused on FOXA1, since it lies within the most frequently amplified genomic region in lung adenocarcinomas. We found that 14q-amplification in NSCLC cell lines was a biomarker for FOXA1 dependency for both in vivo xenograft growth and colony formation, but not mass culture growth in vitro. FOXA1 knockdown identified genes involved in electron transport among the most differentially regulated, indicating FOXA1 loss may lead to a decrease in cellular respiration. In support of this, FOXA1 amplification was correlated with increased sensitivity to the complex I inhibitor phenformin. Integrative ChipSeq analyses reveal that FOXA1 functions in this genetic context may be at least partially independent of...Continue Reading

Datasets Mentioned

BETA
GTX627408
GSE74948
GSE42127
GSE32036
GSE39998
SRP045118

Methods Mentioned

BETA
PCR
DNAseq
transfection
xenograft
Protein Assay
Assay
RNA-Seq
immunoprecipitation
ChIP
ChIP-Seq

Software Mentioned

Picard MarkDuplicates . jar
Motif Scanner
SDS
samtools view - bh - F
DepMap
Bowtie
bowtie2
R package DNAcopy
house
Hypergeometric Optimization of Motif EnRichment ( HOMER )

Related Concepts

Related Feeds

Cancer Genomics (Keystone)

Cancer genomics approaches employ high-throughput technologies to identify the complete catalog of somatic alterations that characterize the genome, transcriptome and epigenome of cohorts of tumor samples. Discover the latest research using such technologies in this feed.