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

Research output: Contribution to journalArticle

43 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1752-1762
Number of pages11
JournalCancer Research
Volume71
Issue number5
DOIs
StatePublished - Mar 1 2011
Externally publishedYes

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Zuo, T., Liu, T. M., Lan, X., Weng, Y. I., Shen, R., Gu, F., Huang, Y. W., Liyanarachchi, S., Deatherage, D. E., Hsu, P. Y., Taslim, C., Ramaswamy, B., Shapiro, C. L., Lin, H. J. L., Cheng, A. S. L., Jin, V. X., & Huang, T. H. M. (2011). Epigenetic silencing mediated through activated PI3K/AKT signaling in breast cancer. Cancer Research, 71(5), 1752-1762. https://doi.org/10.1158/0008-5472.CAN-10-3573