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Updated: Dec 17, 2025

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SREBP1 regulates mitochondrial metabolism in oncogenic KRAS expressing NSCLC

Christian F Ruiz1, Emily D Montal2, John A Haley3

  • 1Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|June 23, 2020
PubMed

Insights

Mutant KRAS in non-small cell lung cancer (NSCLC) upregulates the transcription factor SREBP1. SREBP1 knockdown inhibits cancer cell proliferation and impacts mitochondrial function, independent of lipogenesis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Metabolic Regulation

Background:

  • Cancer cells exhibit metabolic reprogramming to support malignant growth.
  • Mutant KRAS is a key oncogene influencing signaling pathways and tumor metabolism.
  • Oncogenic KRAS promotes de novo lipogenesis in non-small cell lung cancer (NSCLC).

Purpose of the Study:

  • To investigate the role of SREBP1 in KRAS-driven NSCLC metabolism.
  • To elucidate the mechanism by which KRAS influences SREBP1 expression and function.
  • To determine the impact of SREBP1 on cancer cell proliferation and mitochondrial activity.

Main Methods:

  • Genetic knockdown of SREBP1 in mutant KRAS-expressing NSCLC cells.
  • Carbon tracing studies to analyze metabolic pathways.
  • RNA sequencing (RNA-seq) to assess gene expression changes, particularly in mitochondrial components.

Main Results:

  • KRAS was found to increase SREBP1 expression.
  • SREBP1 knockdown significantly inhibited the proliferation of mutant KRAS NSCLC cells.
  • Unexpectedly, lipogenesis was not significantly altered by SREBP1 knockdown.
  • Carbon tracing revealed decreased oxidative phosphorylation.
  • RNA-seq data indicated reduced expression of mitochondrial electron transport chain (ETC) subunits.

Conclusions:

  • SREBP1 plays a crucial role in the proliferation of mutant KRAS NSCLC.
  • SREBP1 has a novel function in regulating mitochondrial function in this cancer model.
  • This function of SREBP1 is distinct from its known role in lipogenesis.
Keywords:
cancer metabolismde novo lipogenesiselectron transport chainoxidative phosphorylation

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