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H3K9 methylation drives resistance to androgen receptor-antagonist therapy in prostate cancer

Mehdi Baratchian1, Ritika Tiwari1, Sirvan Khalighi2

  • 1Genitourinary Malignancies Research Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.

Proceedings of the National Academy of Sciences of the United States of America
|May 18, 2022
PubMed

Insights

Androgen blockade in prostate cancer triggers retroelements (REs), causing interferon responses that inhibit tumor growth. Epigenetic adaptation via H3K9 trimethylation (H3K9me3) silences REs, leading to drug resistance and poor outcomes.

Area of Science:

  • Oncology
  • Epigenetics
  • Immunology

Background:

  • Antiandrogen therapies are standard for prostate cancer but face drug resistance.
  • Mechanisms underlying antiandrogen resistance are not fully understood.

Purpose of the Study:

  • To investigate the epigenetic mechanisms driving antiandrogen resistance in prostate cancer.
  • To identify novel therapeutic targets for overcoming treatment resistance.

Main Methods:

  • Forward genetic screening in a prostate cancer model.
  • Analysis of retroelement (RE) derepression and interferon signaling.
  • Assessment of H3K9 trimethylation (H3K9me3) dynamics and its association with patient outcomes.
  • Pharmacological inhibition of H3K9me3 writers and readers.

Main Results:

  • Androgen blockade induced derepression of retroelements (REs), activating a double-stranded RNA (dsRNA)-stimulated interferon response that suppressed tumor growth.
  • H3K9 trimethylation (H3K9me3) emerged as a key epigenetic adaptation, silencing REs and preventing interferon signaling.
  • Elevated expression of H3K9me3 writers correlated with poor patient response to hormonal therapy.
  • Inhibition of H3K9me3 pathways restored RE expression and blocked antiandrogen resistance.

Conclusions:

  • A novel drug resistance axis involving REs, interferon signaling, and H3K9me3 epigenetic modifications was uncovered.
  • H3K9me3 writers and readers represent potential therapeutic targets to overcome antiandrogen resistance in prostate cancer.
Keywords:
androgensenzalutamideepigeneticshormonal therapyprostate cancer

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