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Regulation of myo-inositol biosynthesis by p53-ISYNA1 pathway

Tomoyuki Koguchi1, Chizu Tanikawa2, Jinichi Mori1

  • 1Laboratory of Clinical Sequence, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.

International Journal of Oncology
|April 2, 2016
PubMed

Insights

The tumor suppressor p53 regulates myo-inositol synthesis by targeting the ISYNA1 gene. This pathway is crucial for p53-mediated tumor suppression and may offer new therapeutic strategies.

Area of Science:

  • Molecular Biology
  • Oncology
  • Biochemistry

Background:

  • The tumor suppressor p53 is known to regulate apoptosis, cell cycle arrest, senescence, and cellular homeostasis.
  • p53's role in energy metabolism, glycolysis, antioxidant effects, and autophagy has been recently elucidated.
  • Its involvement in inositol synthesis, however, remained unexplored.

Purpose of the Study:

  • To investigate the potential role of p53 in regulating myo-inositol biosynthesis.
  • To identify p53 target genes involved in myo-inositol metabolism.
  • To explore the therapeutic implications of this novel p53 function.

Main Methods:

  • Microarray screening to identify p53-induced genes related to myo-inositol metabolism.
  • Cellular experiments using HCT116 p53+/+ and HCT116 p53-/- cells to assess DNA damage effects.
  • Analysis of inositol 3-phosphate synthase (ISYNA1) as a direct p53 target, including its regulatory elements.
  • Functional studies involving ectopic ISYNA1 expression and ISYNA1 knockdown.
  • Correlation analysis of ISYNA1 expression with p53 mutation status in various human cancers.

Main Results:

  • Microarray analysis revealed five p53-induced genes involved in myo-inositol metabolism.
  • DNA damage increased intracellular myo-inositol levels in p53-proficient cells but not in p53-deficient cells.
  • Inositol 3-phosphate synthase (ISYNA1) was identified as a direct p53 target, regulated via a response element in exon 7.
  • Ectopic ISYNA1 expression elevated myo-inositol levels and suppressed tumor cell growth.
  • ISYNA1 knockdown conferred resistance to adriamycin, highlighting its role in p53-mediated growth suppression.
  • ISYNA1 expression correlated significantly with p53 mutations in bladder, breast, head and neck, lung, and pancreatic cancers.

Conclusions:

  • p53 plays a novel role in regulating myo-inositol biosynthesis through direct induction of ISYNA1.
  • This p53-ISYNA1-myo-inositol pathway contributes to tumor suppression.
  • ISYNA1 represents a potential therapeutic target for p53-mutated cancers.

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