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Functional antagonism of chromatin modulators regulates epithelial-mesenchymal transition

Michela Serresi1, Sonia Kertalli2, Lifei Li2

  • 1Max-Delbrück-Center for Molecular Medicine (MDC), Robert-Rössle-Str. 10, 13092 Berlin, Germany. michela.serresi@mdc-berlin.de gaetano.gargiulo@mdc-berlin.de.

Science Advances
|February 25, 2021
PubMed

Insights

Chromatin regulators, not just kinases, significantly impact cancer cell plasticity during epithelial-mesenchymal transition (EMT). This study identifies key regulators controlling EMT and offers new therapeutic targets for lung cancer.

Area of Science:

  • Cancer Biology
  • Epigenetics
  • Molecular Oncology

Background:

  • Epithelial-mesenchymal transition (EMT) is crucial for cancer progression, involving proliferation, migration, and stress response.
  • Kinase signaling is implicated as an EMT driver, but the full molecular mechanisms remain unclear.
  • Understanding the regulators of EMT is vital for developing targeted cancer therapies.

Purpose of the Study:

  • To investigate the role of chromatin regulators in governing epithelial-mesenchymal interconversion.
  • To compare the impact of chromatin regulators with kinases on EMT.
  • To identify specific chromatin regulators involved in homeostatic EMT in lung cancer.

Main Methods:

  • Pharmacological modulation of EMT.
  • Synthetic genetic tracing.
  • CRISPR interference screens to identify key genes.
  • Analysis of chromatin regulators, kinases, RNAPII, and AP-1.

Main Results:

  • Chromatin regulators have a broader impact on EMT than kinases.
  • Several chromatin remodelers, writers, and readers were identified as key regulators of EMT in lung cancer.
  • Loss of specific regulators like ARID1A, DOT1L, BRD2, and ZMYND8 showed complex effects on EMT.
  • These regulators, along with RNAPII and AP-1, control enhancer chromatin of EMT signature genes.

Conclusions:

  • Chromatin regulators play a significant role in controlling cancer cell plasticity and EMT.
  • The identified regulators provide a platform for exploring novel therapeutic strategies targeting tumor-state-specific treatments.
  • This research broadens the understanding of transcriptional control in cancer progression.

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