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Updated: Nov 7, 2025

Direct Measurement of KDM1A Target Engagement Using Chemoprobe-based Immunoassays
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Role for the Histone Demethylase KDM4B in Rhabdomyosarcoma via CDK6 and CCNA2: Compensation by KDM4A and Apoptotic

Zoë S Walters1,2, Ewa Aladowicz1, Barbara Villarejo-Balcells1

  • 1Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, Sutton, London SM2 5NG, UK.

Cancers
|April 30, 2021
PubMed

Insights

Histone demethylase KDM4B drives rhabdomyosarcoma growth but cells adapt. Targeting both KDM4B and KDM4A simultaneously induces apoptosis, suggesting poly-pharmacology for sarcoma treatment.

Area of Science:

  • Epigenetics
  • Cancer Biology
  • Molecular Oncology

Background:

  • Histone demethylases regulate gene expression and are potential cancer therapeutics.
  • Rhabdomyosarcoma (RMS), a pediatric sarcoma, overexpresses histone demethylase family members.
  • RMS cells exhibit sensitivity to the pan-histone demethylase inhibitor JIB-04.

Purpose of the Study:

  • To investigate the role of KDM4B in rhabdomyosarcoma (RMS) cell growth.
  • To explore compensatory mechanisms following KDM4B inhibition.
  • To evaluate combination therapy targeting KDM4B and KDM4A in RMS.

Main Methods:

  • RNA interference (RNAi) screening to identify key histone demethylases.
  • Analysis of cell cycle progression and gene transcription (CDK6, CCNA2).
  • Assessment of KDM4B and KDM4A binding to target gene promoter regions.
  • Evaluation of apoptosis induction by single and dual KDM4B/KDM4A silencing.

Main Results:

  • KDM4B is crucial for RMS cell proliferation, affecting cell cycle and checkpoint gene transcription.
  • Sustained KDM4B knockdown leads to compensatory upregulation of KDM4A.
  • KDM4A compensates for KDM4B by binding to CDK6 and CCNA2 promoters.
  • Simultaneous silencing of KDM4B and KDM4A induces significant RMS cell apoptosis.

Conclusions:

  • KDM4B plays a critical role in RMS cell growth, with KDM4A mediating compensatory mechanisms.
  • Targeting both KDM4B and KDM4A through selective poly-pharmacology is a promising therapeutic strategy for RMS.
  • This approach may overcome resistance and enhance treatment efficacy in rhabdomyosarcoma.
Keywords:
KDM4Bepigeneticshistone demethylasesrhabdomyosarcoma

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