Epigenetic silencing mediated through activated PI3K/AKT signaling in breast cancer

Tao Zuo, Ta Ming Liu, Xun Lan, Yu I. Weng, Rulong Shen, Fei Gu, Yi Wen Huang, Sandya Liyanarachchi, Daniel E. Deatherage, Pei Yin Hsu, Cenny Taslim, Bhuvaneswari Ramaswamy, Charles L. Shapiro, Huey Jen L. Lin, Alfred S.L. Cheng, Victor X. Jin, Tim H.M. Huang

Producción científica: Articlerevisión exhaustiva

52 Citas (Scopus)

Resumen

Trimethylation of histone 3 lysine 27 (H3K27me3) is a critical epigenetic mark for the maintenance of gene silencing. Additional accumulation of DNA methylation in target loci is thought to cooperatively support this epigenetic silencing during tumorigenesis. However, molecular mechanisms underlying the complex interplay between the two marks remain to be explored. Here we show that activation of PI3K/AKT signaling can be a trigger of this epigenetic processing at many downstream target genes. We also find that DNA methylation can be acquired at the same loci in cancer cells, thereby reinforcing permanent repression in those losing the H3K27me3 mark. Because of a link between PI3K/AKT signaling and epigenetic alterations, we conducted epigenetic therapies in conjunction with the signaling-targeted treatment. These combined treatments synergistically relieve gene silencing and suppress cancer cell growth in vitro and in xenografts. The new finding has important implications for improving targeted cancer therapies in the future.

Idioma originalEnglish (US)
Páginas (desde-hasta)1752-1762
Número de páginas11
PublicaciónCancer Research
Volumen71
N.º5
DOI
EstadoPublished - mar 1 2011
Publicado de forma externa

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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