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Targeting the PHF8/YY1 axis suppresses cancer cell growth through modulation of ROS

Xiao-Nan Wu1,2, Jia-Yuan Li1,2, Qi He1,2

  • 1State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361102, China.

Proceedings of the National Academy of Sciences of the United States of America
|January 2, 2024
PubMed

Insights

Protein demethylase PHF8 drives cancer by repressing electron transport chain (ETC) genes. Targeting PHF8 with iPHF8 inhibits cancer cell growth and tumor development by restoring ETC gene expression and reducing mitochondrial ROS.

Area of Science:

  • Epigenetics
  • Cancer Biology
  • Mitochondrial Metabolism

Background:

  • High mitochondrial reactive oxygen species (mROS) levels are implicated in cancer development.
  • The electron transport chain (ETC) tightly regulates mROS, but epigenetic control of ETC gene transcription in cancer is not fully understood.

Purpose of the Study:

  • To investigate the epigenetic mechanisms governing ETC gene transcription in cancer.
  • To identify novel therapeutic targets for cancer treatment.

Main Methods:

  • Overexpression analysis of PHF8 in various cancer types.
  • Investigation of PHF8's role in regulating YY1 methylation and ETC gene expression.
  • Pharmacological inhibition of PHF8 using iPHF8 in cancer cell lines and xenograft models.
  • Assessment of mROS production, cell growth, and tumor suppression.

Main Results:

  • PHF8 is overexpressed in cancers and negatively correlates with ETC gene expression.
  • PHF8 acts as a co-repressor by demethylating transcription factor YY1, suppressing nuclear-coded ETC genes.
  • Pharmacological inhibition of PHF8 (iPHF8) effectively reverses YY1 methylation, restores ETC gene transcription, reduces mROS, and inhibits cancer cell growth.
  • iPHF8 demonstrates potent and safe tumor suppression in vivo xenograft models.

Conclusions:

  • PHF8 epigenetically regulates ETC gene transcription via the PHF8/YY1 axis, promoting mROS production and cancer development.
  • Targeting the PHF8/YY1 axis with iPHF8 represents a promising therapeutic strategy for treating cancers.

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