title: Epigenetic silencing mediated through activated PI3K/AKT signaling in breast cancer.
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.
authors.affiliation: Human Cancer Genetics Program, Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Zuo
authors.forename: Ta-Ming
authors.initials: TM
authors.lastname: Liu
authors.forename: Xun
authors.initials: X
authors.lastname: Lan
authors.forename: Yu-I
authors.initials: YI
authors.lastname: Weng
authors.forename: Rulong
authors.initials: R
authors.lastname: Shen
authors.forename: Fei
authors.initials: F
authors.lastname: Gu
authors.forename: Yi-Wen
authors.initials: YW
authors.lastname: Huang
authors.forename: Sandya
authors.initials: S
authors.lastname: Liyanarachchi
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Deatherage
authors.forename: Pei-Yin
authors.initials: PY
authors.lastname: Hsu
authors.forename: Cenny
authors.initials: C
authors.lastname: Taslim
authors.forename: Bhuvaneswari
authors.initials: B
authors.lastname: Ramaswamy
authors.forename: Charles L
authors.initials: CL
authors.lastname: Shapiro
authors.forename: Huey-Jen L
authors.initials: HJ
authors.lastname: Lin
authors.forename: Alfred S L
authors.initials: AS
authors.lastname: Cheng
authors.forename: Victor X
authors.initials: VX
authors.lastname: Jin
authors.forename: Tim H-M
authors.initials: TH
authors.lastname: Huang
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D020868:Gene Silencing / Q000502:physiology*; D006657:Histones / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D016513:Mice, SCID; D020411:Oligonucleotide Array Sequence Analysis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
chemical_list: D006657:Histones; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt