Investigating Nrf2 function in disease using enrichment analysis predictions and top-down systems biology
Year: 2013
Type: dissertation
Abstract: Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a transcription factor which senses oxidative and electrophile stress.When activated, Nrf2 accumulates in the nucleus, where it induces the expression of cytoprotective target genes.Many diseases are associated with oxidative stress and Nrf2 is therefore a potential therapeutic target.However, Nrf2 has been shown to regulate processes other than redox response and could potentially have diseasepromoting effects.Accumulating evidence suggests that constitutively active Nrf2 has a pivotal role in cancer as it induces pro-survival genes that promote chemoresistance and cancer cell proliferation.Therefore Nrf2 is a novel oncogenic transcription factor, but the prevalence on Nrf2 dysregulation and functions in cancer have not been fully characterized.We analyzed microarray data of over 900 cancer cell lines in Cancer Cell Line Encyclopedia (CCLE) and created an Nrf2 signature model based on our previous microarray data to identify cancers with overactive Nrf2 status.Four novel cancer types and a total of 77 cancer cell lines were discovered by two individual tools to have overactive Nrf2 status with > 95 % probability or FDR of 0.01.Furthermore, we investigated glioma clinical samples in The Cancer Genome Atlas (TCGA) and found characteristic Nrf2 signature in 60 (ca. 10 %) glioblastoma multiforme samples (FDR 0.05).Metabolic changes, such as the Warburg effect have a crucial role in cancer.Nrf2 has been reported to upregulate pentose phosphate pathway in cancer to produce NADPH and molecular building blocks to support cancer cell proliferation and survival.In addition Nrf2 affects the lipid accumulation and synthesis in atherosclerosis and metabolic syndrome mouse models.However, all Nrf2 regulated metabolic pathways have not been identified and little is known about Nrf2-mediated metabolism and its role in disease.We did pathway analysis to our endothelial cell Nrf2 expression data to identify Nrf2 regulated metabolic pathways using human metabolic pathway reconstruction (Recon1).Many previously reported metabolic pathways were enriched, including the pentose phosphate pathway and fatty acid metabolism pathways.Interestingly, cholesterol homeostasis-related pathways, cholesterol metabolism, steroid metabolism and lysosomal transport pathways were also enriched.Cholesterol homeostasis has a significant role in many diseases, including cancer and atherosclerosis; therefore these pathways were further investigated.Many cholesterol pathway genes were downregulated by Nrf2 during the primary response based on our microarray and confirmed by next generation sequencing methods that assayed both primary transcription and mature transcript levels (RNA-and GRO-seq data).However, during secondary response with Nrf2 overexpression data, many cholesterol pathway genes were upregulated.No direct Nrf2 targeted regulatory elements were found, suggesting that Nrf2 regulates cholesterol homeostasis indirectly.In these computational analyses, publicly available data was integrated with our own data to do unbiased hypothesis tests to understand Nrf2 role in disease.The results motivate several initial conclusions to be investigated further.
Author: Petri Pölönen
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: Itä-Suomen Yliopisto, Tampereen Yliopisto
OpenAlex ID: W3097207760