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SREBP1 regulates mitochondrial metabolism in oncogenic KRAS expressing NSCLC
Author(s) -
Ruiz Christian F.,
Montal Emily D.,
Haley John A.,
Bott Alex J.,
Haley John D.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.202000052r
Subject(s) - lipogenesis , kras , gene knockdown , sterol regulatory element binding protein , cancer research , pi3k/akt/mtor pathway , downregulation and upregulation , biology , microbiology and biotechnology , chemistry , lipid metabolism , transcription factor , signal transduction , biochemistry , apoptosis , mutation , gene
Cancer cells require extensive metabolic reprograming in order to provide the bioenergetics and macromolecular precursors needed to sustain a malignant phenotype. Mutant KRAS is a driver oncogene that is well‐known for its ability to regulate the ERK and PI3K signaling pathways. However, it is now appreciated that KRAS can promote the tumor growth via upregulation of anabolic metabolism. We recently reported that oncogenic KRAS promotes a gene expression program of de novo lipogenesis in non‐small cell lung cancer (NSCLC). To define the mechanism(s) responsible, we focused on the lipogenic transcription factor SREBP1. We observed that KRAS increases SREBP1 expression and genetic knockdown of SREBP1 significantly inhibited the cell proliferation of mutant KRAS ‐expressing cells. Unexpectedly, lipogenesis was not significantly altered in cells subject to SREBP1 knockdown. Carbon tracing metabolic studies showed a significant decrease in oxidative phosphorylation and RNA‐seq data revealed a significant decrease in mitochondrial encoded subunits of the electron transport chain (ETC). Taken together, these data support a novel role, distinct from lipogenesis, of SREBP1 on mitochondrial function in mutant KRAS NSCLC.