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

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 (2022)

Publication Type: Journal article

Publication year: 2022

Journal

Developmental Cell Elsevier (Cell Press)

Book Volume: 57

Pages Range: 310-328.e9

Journal Issue: 3

DOI: 10.1016/j.devcel.2022.01.006

Abstract

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.

Authors with CRIS profile

Aline Bozec Professur für Experimentelle Immuntherapie

Involved external institutions

Duke University US United States (USA) (US) Universidad de Navarra ES Spain (ES) Duke University Medical Center US United States (USA) (US)

How to cite

APA:

Kadur Lakshminarasimha Murthy, P., Xi, R., Arguijo, D., Everitt, J.I., Kocak, D.D., Kobayashi, Y.,... Shen, X. (2022). Epigenetic basis of oncogenic-Kras-mediated epithelial-cellular proliferation and plasticity. Developmental Cell, 57(3), 310-328.e9. https://dx.doi.org/10.1016/j.devcel.2022.01.006

MLA:

Kadur Lakshminarasimha Murthy, Preetish, et al. "Epigenetic basis of oncogenic-Kras-mediated epithelial-cellular proliferation and plasticity." Developmental Cell 57.3 (2022): 310-328.e9.

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