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Phosphorylated nuclear DICER1 promotes open chromatin state and lineage plasticity of AT2 tumor cells in lung

Raisa A Reyes-Castro1,2,3, Shin-Yu Chen1, Jacob Seemann1

  • 1Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Science Advances
|July 26, 2023
PubMed

Insights

Phosphorylated DICER1 in the nucleus drives advanced lung cancer progression in mice, independent of microRNAs and EMT. This nuclear DICER1 reprograms tumor cells by altering chromatin, promoting a lineage shift that contributes to tumorigenesis.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Biology

Background:

  • The KRAS/ERK pathway influences DICER1 phosphorylation and nuclear translocation, contributing to tumorigenesis.
  • The precise mechanisms by which phosphorylated DICER1 (phospho-DICER1) drives tumor progression are not fully understood.
  • DICER1's canonical roles involve microRNA (miRNA) regulation and epithelial-to-mesenchymal transition (EMT).

Purpose of the Study:

  • To investigate the role of phospho-nuclear DICER1 in late-stage lung tumor progression.
  • To elucidate the mechanisms by which phospho-nuclear DICER1 promotes cancer, independent of canonical miRNA and EMT pathways.
  • To identify the molecular components and cellular processes involved in phospho-nuclear DICER1-mediated lung cancer progression.

Main Methods:

  • Utilized a mouse model with oncogenic Kras to study lung tumor progression.
  • Analyzed chromatin compaction and gene expression in murine AT2 tumor cells.
  • Investigated the expression of phospho-nuclear DICER1 and gastric genes in human lung adenocarcinoma (LUAD) samples.
  • Characterized a multimeric chromatin-DICER1 complex involving Mediator complex subunit 12, CBX1, and MACROH2A.1.

Main Results:

  • Phospho-nuclear DICER1 promotes late-stage tumor progression in a Kras-driven mouse model, independent of miRNAs and EMT.
  • Altered chromatin compaction and expression of gastric genes were observed in advanced murine lung tumors.
  • Tumor cells exhibited a lineage transition from alveolar to endodermal states.
  • Human LUADs with advanced disease showed co-expression of phospho-nuclear DICER1 and gastric genes.

Conclusions:

  • Phospho-nuclear DICER1 drives lung cancer progression through lineage reprogramming of AT2 tumor cells.
  • This reprogramming involves altered chromatin structure and the formation of a chromatin-DICER1 complex.
  • The findings reveal a novel, non-canonical mechanism for DICER1 in mediating lung cancer progression and suggest potential therapeutic targets.

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