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DNA Methyltransferase 1 Targeting Using Guadecitabine Inhibits Prostate Cancer Growth by an Apoptosis-Independent

Dev Karan1, Manohar Singh1, Seema Dubey1

  • 1Department of Pathology, MCW Cancer Center, Prostate Cancer Center of Excellence, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.

Cancers
|June 22, 2023
PubMed

Insights

Guadecitabine (gDEC) inhibits prostate cancer growth by depleting DNA methyltransferase 1 (DNMT1) and upregulating epigenetic enzymes. This epigenetic drug promotes cell cycle exit independent of apoptosis, showing promise in preclinical models.

Area of Science:

  • Epigenetics
  • Cancer Biology
  • Pharmacology

Background:

  • Epigenetic alterations, including DNA methylation and histone modifications, play a crucial role in suppressing tumor suppressor genes during prostate cancer progression.
  • DNA methyltransferase 1 (DNMT1) is a key enzyme responsible for DNA methylation and is often dysregulated in cancer.

Purpose of the Study:

  • To investigate the anti-prostate cancer effects of the small molecule drug guadecitabine (gDEC), which inhibits and depletes DNMT1.
  • To elucidate the molecular mechanisms underlying gDEC's anti-cancer activity in prostate cancer models.

Main Methods:

  • In vitro studies using prostate cancer cell lines (LNCaP, 22Rv1, MDA PCa 2b) to assess cell growth, proliferation, apoptosis, and epithelial-mesenchymal transition (EMT) markers.
  • In vivo studies using mouse xenograft models (22Rv1, MDA PCa 2b, PC-3) to evaluate tumor growth inhibition and toxicity.
  • Molecular analyses including DNMT1 depletion confirmation, EMT marker assessment, androgen receptor (AR) and AR-variant 7 (AR-V7) expression, and PCR array analysis of chromatin modifying enzymes.

Main Results:

  • Guadecitabine (gDEC) inhibited prostate cancer cell growth and proliferation in vitro without inducing apoptosis.
  • gDEC treatment led to DNMT1 depletion and modulated EMT markers (E-cadherin, β-catenin) in prostate cancer cell lines.
  • In vivo, gDEC significantly inhibited tumor growth in multiple prostate cancer xenograft models without observable toxicity.
  • gDEC did not affect AR or AR-V7 expression and did not sensitize cells to enzalutamide.
  • gDEC upregulated several lysine-specific methyltransferases (KMTs) and increased global histone 3 lysine 4 mono- and di-methylation (H3K4me1, H3K4me2).

Conclusions:

  • Guadecitabine (gDEC) demonstrates significant anti-prostate cancer effects both in vitro and in vivo by depleting DNMT1.
  • gDEC's mechanism involves upregulation of activating epigenetic enzymes, promoting epithelial program activation, and inducing cell cycle exit independently of apoptosis.
  • These findings suggest gDEC as a potential epigenetic therapeutic agent for prostate cancer, acting through novel mechanisms.
Keywords:
DNMT1H3K4 methylationguadecitabineprostate cancer

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