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KDM4B as a target for prostate cancer: structural analysis and selective inhibition by a novel inhibitor

Chia-Han Chu1, Ling-Yu Wang, Kai-Cheng Hsu

  • 1Institute of Molecular and Cellular Biology and Department of Life Sciences and ‡Biomedical Science and Engineering Center, National Tsing-Hua University , Hsinchu, 30013, Taiwan.

Journal of Medicinal Chemistry
|June 28, 2014
PubMed

Insights

Histone demethylases KDM4A/KDM4B are key drivers in prostate cancer. A novel inhibitor blocks cancer cell viability by increasing H3K9me3 levels and silencing growth genes.

Area of Science:

  • Biochemistry and Molecular Biology
  • Cancer Research
  • Epigenetics

Background:

  • Jumonji C-containing histone lysine demethylases (KDM4A-KDM4D) regulate gene transcription and genome stability by removing methyl groups from H3K9/H3K36.
  • KDM4A and KDM4B are overexpressed in prostate cancer and linked to androgen receptor (AR) signaling, suggesting their role as progression factors.

Purpose of the Study:

  • To elucidate the structural basis of KDM4B activity and identify selective inhibitors for KDM4A/KDM4B.
  • To investigate the therapeutic potential of KDM4A/KDM4B inhibition in prostate cancer.

Main Methods:

  • Crystal structure determination of the KDM4B·pyridine 2,4-dicarboxylic acid·H3K9me3 ternary complex.
  • Virtual screening to identify selective KDM4A/KDM4B inhibitors.
  • Pharmacological and genetic inhibition assays in cultured prostate cancer cells.

Main Results:

  • The crystal structure revealed the active site and K9/K36 demethylation specificity of KDM4B.
  • A selective KDM4A/KDM4B inhibitor (compound 4) was identified via virtual screening.
  • Inhibition of KDM4A/KDM4B reduced prostate cancer cell viability, increased H3K9me3 levels, and silenced AR-responsive genes.

Conclusions:

  • KDM4A/KDM4B are critical activators of AR signaling and potential therapeutic targets in prostate cancer.
  • The identified inhibitor scaffold offers a promising new strategy for prostate cancer treatment.

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