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Updated: May 1, 2026

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KDM4B/DHX9 promotes chemoresistance in small-cell lung cancer through the MYCN-driven signaling pathway

Qiong Lyu1,2,3, Huiying Liu2, Weitao Shen2

  • 1Department of Oncology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China.

Oncogene
|April 29, 2026
PubMed

Insights

Histone demethylase KDM4B drives chemoresistance in small cell lung cancer (SCLC) by activating the Hedgehog pathway. Targeting KDM4B or its interaction with DHX9 offers a potential strategy to restore chemosensitivity in SCLC patients.

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • Small cell lung cancer (SCLC) frequently develops chemoresistance, linked to epigenetic alterations.
  • Histone demethylases are implicated in chemoresistance, but their specific roles in SCLC require systematic investigation.

Purpose of the Study:

  • To systematically identify histone demethylases involved in SCLC chemoresistance.
  • To elucidate the molecular mechanisms by which identified demethylases contribute to chemoresistance.
  • To explore therapeutic strategies targeting identified pathways for overcoming SCLC chemoresistance.

Main Methods:

  • Generation of chemoresistant SCLC cell lines through dose escalation.
  • RNA sequencing and bioinformatic analyses (linear regression, meta-analysis) to identify key genes.
  • Validation in neuroendocrine SCLC models and immunohistochemical analysis of patient tissues.
  • In vitro and in vivo experiments to assess the efficacy of targeting KDM4B/DHX9 interactions.

Main Results:

  • KDM4B was identified as a key driver of chemoresistance in SCLC.
  • Elevated KDM4B expression was observed in chemoresistant SCLC tissues.
  • KDM4B promotes chemoresistance via the Hedgehog pathway, enhancing proliferation and stemness.
  • KDM4B interacts with DHX9 to activate MYCN transcription and the Hedgehog pathway.
  • DHX9 inhibition showed synergistic effects with chemotherapy and restored chemosensitivity.

Conclusions:

  • KDM4B is a critical mediator of SCLC chemoresistance through the Hedgehog/MYCN axis.
  • Targeting the KDM4B-DHX9 interaction presents a promising therapeutic avenue for overcoming SCLC chemoresistance.
  • Further investigation into KDM4B's role in neuroendocrine SCLC subtypes is warranted.

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