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A Ras-LSD1 axis activates PI3K signaling through PIK3IP1 suppression

Kyunghee Lee1,2, Mayumi Kitagawa3,4, Pei Ju Liao3

  • 1Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, 169857, Singapore. khee0326@hotmail.com.

Oncogenesis
|January 5, 2020
PubMed

Insights

Activated Ras suppresses PIK3IP1 expression, promoting cancer growth. This study reveals Ras recruits LSD1 to inhibit PIK3IP1 transcription, highlighting a key mechanism in cancer progression.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Epigenetics

Background:

  • PI3K Interacting Protein 1 (PIK3IP1) suppresses the PI3K/Akt/mTOR pathway.
  • Activated Ras is known to suppress PIK3IP1 expression, promoting the PI3K pathway in cancer cells.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which Ras activation leads to the loss of PIK3IP1 expression.
  • To confirm the role of PIK3IP1 in suppressing Ras-induced transformation.

Main Methods:

  • Utilized doxycycline-inducible PIK3IP1 expression system.
  • Investigated the recruitment of lysine-specific demethylase 1 (LSD1) to the PIK3IP1 gene.
  • Analyzed histone marks at the PIK3IP1 promoter and enhancer regions.

Main Results:

  • Inducing PIK3IP1 expression reversed Ras-induced anchorage-independent growth, confirming PIK3IP1's role in transformation.
  • Ras activity was found to repress PIK3IP1 expression by recruiting LSD1 to its gene promoter and enhancer.
  • This recruitment resulted in the erasure of active histone marks, suppressing PIK3IP1 transcription.

Conclusions:

  • Ras decommissions PIK3IP1 gene expression through enhanced LSD1 recruitment and corepressor activity.
  • This mechanism involves cross-activation between Ras/Raf/MEK/ERK and PI3K/AKT/mTOR pathways.
  • Understanding this pathway provides insights into cancer development and potential therapeutic targets.

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