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RAD21-mediated epigenetic regulation promotes lung adenocarcinoma progression and sensitizes cancer cells to

Chu Xiao1, Tao Fan1, Di Wang1

  • 1Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.

Cancer Letters
|September 26, 2025
PubMed

Insights

High RAD21 protein levels in lung adenocarcinoma (LUAD) drive cancer progression and metastasis. Targeting RAD21 or its downstream pathways, like MAPK/ERK, shows promise for new LUAD therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • The cohesin complex, including RAD21, is crucial for chromatin organization and gene regulation.
  • RAD21 is frequently amplified and overexpressed in lung adenocarcinoma (LUAD), but its role is not fully understood.

Purpose of the Study:

  • To investigate the functional mechanisms of RAD21 in LUAD progression.
  • To explore the therapeutic potential of targeting RAD21 or its associated pathways.

Main Methods:

  • Survival analysis and immunohistochemistry to assess RAD21 protein levels and patient prognosis.
  • Genetic depletion of RAD21 in LUAD cells.
  • RNA-sequencing and ChIP-sequencing to analyze gene expression and RAD21 binding sites.
  • In vitro and in vivo metastasis assays.
  • Pharmacological inhibition of ERK signaling with ulixertinib.

Main Results:

  • High RAD21 protein levels correlate with poor LUAD patient prognosis.
  • RAD21 depletion inhibits LUAD cell proliferation, induces cell cycle arrest and apoptosis, and reduces metastasis.
  • RAD21 regulates genes involved in MAPK signaling and epithelial-mesenchymal transition (EMT).
  • RAD21 depletion represses EMT, focal adhesion, and MAPK/ERK activation.
  • RAD21 modulates H3K4me3, leading to transcriptional dysregulation of cancer-associated genes.
  • Ulixertinib effectively reverses RAD21-driven metastasis, especially in KRAS-mutant LUAD.

Conclusions:

  • RAD21 acts as a key epigenetic regulator driving LUAD progression and metastasis.
  • Targeting RAD21-mediated pathways, particularly ERK signaling, offers a promising therapeutic strategy for LUAD, with potential benefits in KRAS-mutant cases.
Keywords:
CohesinERKLung adenocarcinomaRAD21Ulixertinib

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