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The DNMT1-PAS1-PH20 axis drives breast cancer growth and metastasis

Yenan Fu1, Xi Zhang1, Xiao Liu2

  • 1Program for Cancer and Cell Biology, Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, PKU International Cancer Institute; MOE Key Laboratory of Carcinogenesis and Translational Research and State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing, 100191, China.

Signal Transduction and Targeted Therapy
|March 21, 2022
PubMed

Insights

Decitabine, a DNA methyltransferase inhibitor, suppresses breast cancer progression by activating the long non-coding RNA PHACTR2-AS1 (PAS1), which silences PH20 expression. This DNMT1-PAS1-PH20 axis offers a novel therapeutic target for breast cancer.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Epigenetics

Background:

  • PH20 hyaluronidase degrades extracellular matrix hyaluronan and influences tumor progression.
  • DNA methyltransferase (DNMT) inhibition elevates hyaluronan, but its effect on PH20 is unknown.

Purpose of the Study:

  • To investigate if DNMT inhibitors, specifically decitabine, regulate PH20 expression.
  • To elucidate the molecular mechanism by which decitabine affects PH20 and its role in breast cancer.

Main Methods:

  • Investigated decitabine's effect on PH20 expression.
  • Identified the role of long non-coding RNA PHACTR2-AS1 (PAS1) in mediating decitabine's action.
  • Characterized the interaction of PAS1 with vigilin and SUV39H1.
  • Analyzed H3K9 methylation of PH20.
  • Evaluated the therapeutic potential of decitabine and PAS1-based combination therapy in mouse models.

Main Results:

  • Decitabine suppresses PH20 expression by activating PAS1.
  • PAS1 forms a complex with vigilin for stability and recruits SUV39H1 to methylate and silence PH20.
  • PAS1 inhibits breast cancer growth and metastasis by suppressing PH20.
  • Combination therapy with decitabine and PAS1-30nt-RNA effectively inhibited breast cancer growth and metastasis in mice.

Conclusions:

  • DNMT1, PAS1, and PH20 form a regulatory axis controlling breast cancer growth and metastasis.
  • The DNMT1-PAS1-PH20 axis represents a potential therapeutic target for breast cancer treatment.

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