Epigenetic silencing mediated through activated PI3K/AKT signaling in breast cancer. Cancer Res 2011 Mar 01;71(5):1752-62
Date
01/11/2011Pubmed ID
21216892Pubmed Central ID
PMC3048165DOI
10.1158/0008-5472.CAN-10-3573Scopus ID
2-s2.0-79952241034 (requires institutional sign-in at Scopus site) 51 CitationsAbstract
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.
Author List
Zuo T, Liu TM, Lan X, Weng YI, Shen R, Gu F, Huang YW, Liyanarachchi S, Deatherage DE, Hsu PY, Taslim C, Ramaswamy B, Shapiro CL, Lin HJ, Cheng AS, Jin VX, Huang THAuthor
Victor X. Jin PhD Professor in the Institute for Health and Equity department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBreast Neoplasms
Cell Line, Tumor
DNA Methylation
Female
Gene Expression
Gene Expression Regulation, Neoplastic
Gene Silencing
Histones
Humans
Immunohistochemistry
Mice
Mice, SCID
Oligonucleotide Array Sequence Analysis
Phosphatidylinositol 3-Kinases
Proto-Oncogene Proteins c-akt
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction
Xenograft Model Antitumor Assays