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Targeting KDM6A Suppresses SREBP1c-Dependent Lipid Metabolism and Prostate Tumorigenesis

Donge Tang1,2, Yong Dai2, Songhui Xu3

  • 1Research Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.

Cancer Research
|October 14, 2021
PubMed

Insights

The histone demethylase KDM6A drives prostate cancer by boosting lipid metabolism via SREBP1c. Inhibiting USP7 to reduce KDM6A levels suppresses tumor growth and enhances treatment efficacy.

Area of Science:

  • Epigenetics
  • Cancer Biology
  • Molecular Oncology

Background:

  • KDM6A is a histone demethylase regulating gene expression and involved in development and cancer.
  • Prostate cancer progression is linked to epigenetic alterations and metabolic dysregulation.

Purpose of the Study:

  • To investigate the role of KDM6A in prostate cancer initiation and progression.
  • To elucidate the molecular mechanisms by which KDM6A influences prostate tumorigenesis.
  • To evaluate the therapeutic potential of targeting the USP7/KDM6A axis.

Main Methods:

  • Utilized conditional knockout mouse models with specific deletion of KDM6A in prostate epithelium.
  • Investigated KDM6A's interaction with the SREBP1c promoter.
  • Assessed the impact of USP7 inhibition on KDM6A stability and prostate cancer growth in vivo (xenograft models).

Main Results:

  • KDM6A deletion significantly inhibited PTEN-loss-initiated prostate tumor progression.
  • KDM6A promotes tumorigenesis and lipid metabolism by increasing SREBP1c transcription.
  • USP7 deubiquitinates KDM6A, enhancing its expression; KDM6A is upregulated in prostate cancer and linked to USP7.
  • Inhibiting USP7 suppressed tumor growth and improved KDM6A inhibitor efficacy.

Conclusions:

  • KDM6A is essential for prostate tumorigenesis, regulating lipid metabolism via SREBP1c.
  • The USP7/KDM6A axis represents a promising therapeutic target for prostate cancer.
  • Targeting USP7/KDM6A may overcome therapeutic resistance in prostate cancer treatment.

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