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p15(INK4b) in HDAC inhibitor-induced growth arrest

Toshiaki Hitomi1, Youichirou Matsuzaki, Tomoya Yokota

  • 1Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.

FEBS Letters
|November 19, 2003
PubMed

Insights

Histone deacetylase (HDAC) inhibitors activate the p15(INK4b) gene, independent of p21(WAF1/Cip1). This suggests p15(INK4b) is a key target for HDAC inhibitors, impacting tumor cell growth.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Cycle Regulation

Background:

  • Histone deacetylase (HDAC) inhibitors are known to arrest tumor cells at the G1 phase and activate p21(WAF1/Cip1).
  • Evidence suggests a p21(WAF1/Cip1)-independent pathway mediating HDAC inhibitor effects.

Purpose of the Study:

  • To investigate the role of the p15(INK4b) gene in HDAC inhibitor-induced cell cycle arrest.
  • To identify novel molecular targets of HDAC inhibitors beyond p21(WAF1/Cip1).

Main Methods:

  • Treatment of HaCaT cells with HDAC inhibitors (trichostatin A and sodium butyrate).
  • Analysis of p15(INK4b) gene activation via its promoter.
  • Assessment of cell growth inhibition in HCT116 p21 knockout cells.

Main Results:

  • HDAC inhibitors, TSA and sodium butyrate, were found to activate the p15(INK4b) gene in HaCaT cells.
  • Upregulation of p15(INK4b) by TSA correlated with growth inhibition in HCT116 p21 (-/-) cells.
  • These findings highlight a p21(WAF1/Cip1)-independent mechanism involving p15(INK4b).

Conclusions:

  • The p15(INK4b) gene is a significant molecular target of HDAC inhibitors.
  • p15(INK4b) activation represents a crucial pathway in HDAC inhibitor-mediated anti-cancer effects.
  • This study expands the understanding of HDAC inhibitor mechanisms in cancer therapy.

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