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Epigenetic basis of oncogenic-Kras-mediated epithelial-cellular proliferation and plasticity

Preetish Kadur Lakshminarasimha Murthy1, Rui Xi2, Diana Arguijo3

  • 1Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA; Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca, NY 14853, USA; Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.

Developmental Cell
|February 8, 2022
PubMed

Insights

Oncogenic Kras mutations drive cancer by altering cell proliferation and identity. A FOSL1-based AP-1 factor controls chromatin remodeling, essential for neoplastic transformation in Kras-mutant cells.

Area of Science:

  • Molecular biology
  • Cancer research
  • Epigenetics

Background:

  • Oncogenic Kras mutations promote uncontrolled cell growth and tissue neoplasms.
  • Kras-driven carcinogenesis involves lineage transformation, but the molecular timeline is unclear.

Purpose of the Study:

  • To elucidate the molecular events and epigenetic mechanisms driving Kras-induced neoplastic transformation.
  • To investigate the role of transcription factors and chromatin remodeling in Kras-mutant cells.

Main Methods:

  • Utilized mouse models, primary human tissues, and cell lines.
  • Analyzed Kras-mutant alveolar type II cells (AEC2) and distal airway club cells.
  • Investigated the function of FOSL1-based AP-1 and the mSWI/SNF complex in chromatin accessibility.

Main Results:

  • In Kras-mutant AEC2, FOSL1-AP-1 directs mSWI/SNF to remodel chromatin, enabling expression of oncogenic transformation genes.
  • Kras-mutant club cells undergo transdifferentiation via NKX2.1 and oncogenic transformation via AP-1.
  • A conserved AP-1-dependent chromatin remodeling program regulates carcinogenesis across tissues.

Conclusions:

  • Neoplasms retain epigenetic memory of their cell of origin.
  • Cell-type-specific transcription factors and AP-1-mediated chromatin remodeling are critical in Kras-driven cancer.
Keywords:
ATAC-seqFosl1KRASNSCLCadenocarcinomaalveolar type II cellclub cellepigeneticsintestinal stem celllung

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