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Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors
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DNMT1 and DNMT3B regulate tumorigenicity of human prostate cancer cells by controlling RAD9 expression through

Aiping Zhu1, Kevin M Hopkins1, Richard A Friedman2,3

  • 1Center for Radiological Research, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.

Carcinogenesis
|August 12, 2020
PubMed

Insights

High RAD9 protein levels drive prostate cancer growth and metastasis. DNA methyltransferases DNMT1 and DNMT3B cause this by hypermethylating RAD9, offering a potential therapeutic target for prostate cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Prostate cancer is a leading cause of cancer death in men.
  • RAD9 protein stabilizes the genome but is overproduced in prostate cancer.
  • RAD9 overproduction is critical for prostate cancer progression and metastasis.

Purpose of the Study:

  • To investigate the regulatory mechanisms behind RAD9 overproduction in prostate cancer.
  • To determine the role of DNA methyltransferases (DNMTs) in RAD9 regulation.
  • To explore the potential of targeting RAD9 or its regulators for prostate cancer therapy.

Main Methods:

  • Analysis of RAD9, DNMT1, and DNMT3B levels in prostate cancer cell lines (DU145, CWR22, LNCaP, PC-3) and tumors.
  • Investigating the effect of DNMT inhibition (shRNA) on RAD9 expression and tumorigenicity in DU145 cells.
  • Assessing the impact of RAD9 re-expression in DNMT-knockdown cells.
  • Correlating RAD9, DNMT levels, and RAD9 promoter methylation in clinical prostate tumor samples.

Main Results:

  • RAD9, DNMT1, and DNMT3B are highly abundant in prostate cancer cells.
  • CpG hypermethylation in RAD9 intron 2 drives high RAD9 expression in DU145 cells.
  • DNMT1 and DNMT3B target this suppressor site in DU145 cells, where methylation is key for RAD9 regulation.
  • Reducing DNMT1 or DNMT3B decreased RAD9 levels and tumorigenicity; RAD9 re-expression restored tumorigenicity.
  • High RAD9, DNMT1, DNMT3B, and RAD9 promoter hypermethylation strongly correlated in prostate tumors.

Conclusions:

  • RAD9 is epigenetically regulated by DNMT1 and DNMT3B through targeted hypermethylation in prostate cancer.
  • Consequent RAD9 overproduction promotes prostate tumorigenesis.
  • This epigenetic pathway represents a novel therapeutic strategy for prostate cancer.

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