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FK228 induces mitotic catastrophe in A549 cells by mistargeting chromosomal passenger complex localization through

Xuhui Zhang1, Zhiyi Zhang, Guozhu Chen

  • 1Department of Pathology, Beijing Institute of Basic Medical Sciences, China.

Acta Biochimica Et Biophysica Sinica
|September 7, 2010
PubMed

Insights

Histone deacetylase inhibitors (HDACis) kill cancer cells by disrupting centromere function. FK228 causes epigenetic changes, impairing chromosomal passenger complex (CPC) recruitment and leading to mitotic catastrophe.

Area of Science:

  • Epigenetics
  • Cancer Biology
  • Cellular Mitosis

Background:

  • Histone deacetylase inhibitors (HDACis) are known to induce cancer cell death.
  • HDACis can cause mitotic catastrophe, a form of cell death, linked to improper chromosomal passenger complex (CPC) localization at the centromere.
  • The precise molecular mechanisms underlying these effects remain incompletely understood.

Purpose of the Study:

  • To elucidate the epigenetic mechanisms by which HDAC inhibitors affect centromere function and induce mitotic catastrophe in cancer cells.
  • To investigate the impact of a specific HDAC inhibitor, FK228, on centromeric epigenetic modifications.

Main Methods:

  • Treatment of cancer cells with the HDAC inhibitor FK228.
  • Analysis of key epigenetic modifications at the centromere, including histone H3 acetylation (H3K9), histone H3 lysine 9 trimethylation (H3K9me3), histone H3 serine 10 phosphorylation (H3S10ph), and centromere protein A (CENP-A) levels.
  • Assessment of chromosomal passenger complex (CPC) localization and centromere function.

Main Results:

  • FK228 induced significant epigenetic alterations at the centromere.
  • Specifically, FK228 enhanced histone H3 lysine 9 acetylation (H3K9ac) and decreased H3K9 trimethylation (H3K9me3).
  • FK228 also led to decreased phosphorylation of histone H3 serine 10 (H3S10ph) and reduced levels of centromere protein A (CENP-A), ultimately inhibiting CPC recruitment and causing aberrant mitosis.

Conclusions:

  • Hyperacetylation of H3K9, induced by FK228, inhibits CPC recruitment to the centromere.
  • This impaired CPC recruitment leads to defective centromere assembly and function, resulting in mitotic catastrophe.
  • Hypoacetylation of histone in the pericentromere is crucial for CPC recruitment and mediating mitotic catastrophe in HDACi-treated cancer cells.

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