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

Journal Article (Journal Article)

Oncogenic Kras induces a hyper-proliferative state that permits cells to progress to neoplasms in diverse epithelial tissues. Depending on the cell of origin, this also involves lineage transformation. Although a multitude of downstream factors have been implicated in these processes, the precise chronology of molecular events controlling them remains elusive. Using mouse models, primary human tissues, and cell lines, we show that, in Kras-mutant alveolar type II cells (AEC2), FOSL1-based AP-1 factor guides the mSWI/SNF complex to increase chromatin accessibility at genomic loci controlling the expression of genes necessary for neoplastic transformation. We identified two orthogonal processes in Kras-mutant distal airway club cells. The first promoted their transdifferentiation into an AEC2-like state through NKX2.1, and the second controlled oncogenic transformation through the AP-1 complex. Our results suggest that neoplasms retain an epigenetic memory of their cell of origin through cell-type-specific transcription factors. Our analysis showed that a cross-tissue-conserved AP-1-dependent chromatin remodeling program regulates carcinogenesis.

Full Text

Duke Authors

Cited Authors

  • Kadur Lakshminarasimha Murthy, P; Xi, R; Arguijo, D; Everitt, JI; Kocak, DD; Kobayashi, Y; Bozec, A; Vicent, S; Ding, S; Crawford, GE; Hsu, D; Tata, PR; Reddy, T; Shen, X

Published Date

  • February 7, 2022

Published In

Volume / Issue

  • 57 / 3

Start / End Page

  • 310 - 328.e9

PubMed ID

  • 35134344

Pubmed Central ID

  • PMC8938988

Electronic International Standard Serial Number (EISSN)

  • 1878-1551

Digital Object Identifier (DOI)

  • 10.1016/j.devcel.2022.01.006

Language

  • eng

Conference Location

  • United States