AURKB promotes colorectal cancer progression by triggering the phosphorylation of histone H3 at serine 10 to activate CCNE1 expression

Aging (Albany NY). 2024 May 6;16(9):8019-8030. doi: 10.18632/aging.205801. Epub 2024 May 6.

Abstract

Aurora kinase B (AURKB) initiates the phosphorylation of serine 10 on histone H3 (pH3S10), a crucial process for chromosome condensation and cytokinesis in mammalian mitosis. Nonetheless, the precise mechanisms through which AURKB regulates the cell cycle and contributes to tumorigenesis as an oncogenic factor in colorectal cancer (CRC) remain unclear. Here, we report that AURKB was highly expressed and positively correlated with Ki-67 expression in CRC. The abundant expression of AURKB promotes the growth of CRC cells and xenograft tumors in animal model. AURKB knockdown substantially suppressed CRC proliferation and triggered cell cycle arrest in G2/M phase. Interestingly, cyclin E1 (CCNE1) was discovered as a direct downstream target of AURKB and functioned synergistically with AURKB to promote CRC cell proliferation. Mechanically, AURKB activated CCNE1 expression by triggering pH3S10 in the promoter region of CCNE1. Furthermore, it was showed that the inhibitor specific for AURKB (AZD1152) can suppress CCNE1 expression in CRC cells and inhibit tumor cell growth. To conclude, this research demonstrates that AURKB accelerated the tumorigenesis of CRC through its potential to epigenetically activate CCNE1 expression, suggesting AURKB as a promising therapeutic target in CRC.

Keywords: AURKB; CCNE1; cell cycle; colorectal cancer; polyploidy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aurora Kinase B* / genetics
  • Aurora Kinase B* / metabolism
  • Cell Line, Tumor
  • Cell Proliferation* / genetics
  • Colorectal Neoplasms* / genetics
  • Colorectal Neoplasms* / metabolism
  • Colorectal Neoplasms* / pathology
  • Cyclin E* / genetics
  • Cyclin E* / metabolism
  • Disease Progression
  • Female
  • Gene Expression Regulation, Neoplastic
  • Histones* / metabolism
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Oncogene Proteins* / genetics
  • Oncogene Proteins* / metabolism
  • Phosphorylation
  • Serine / metabolism

Substances

  • CCNE1 protein, human
  • AURKB protein, human