The Chromatin Assembly Factor Complex 1 (CAF1) and 5-Azacytidine (5-AzaC) Affect Cell Motility in Src-transformed Human Epithelial Cells

Akinori Endo, Tony Ly, Raffaella Pippa, Dalila Bensaddek, Armel Nicolas, Angus I Lamond

Research output: Contribution to journalArticlepeer-review

Abstract

Tumor invasion into surrounding stromal tissue is a hallmark of high grade, metastatic cancers. Oncogenic transformation of human epithelial cells in culture can be triggered by activation of v-Src kinase, resulting in increased cell motility, invasiveness, and tumorigenicity and provides a valuable model for studying how changes in gene expression cause cancer phenotypes. Here, we show that epithelial cells transformed by activated Src show increased levels of DNA methylation and that the methylation inhibitor 5-azacytidine (5-AzaC) potently blocks the increased cell motility and invasiveness induced by Src activation. A proteomic screen for chromatin regulators acting downstream of activated Src identified the replication-dependent histone chaperone CAF1 as an important factor for Src-mediated increased cell motility and invasion. We show that Src causes a 5-AzaC-sensitive decrease in both mRNA and protein levels of the p150 (CHAF1A) and p60 (CHAF1B), subunits of CAF1. Depletion of CAF1 in untransformed epithelial cells using siRNA was sufficient to recapitulate the increased motility and invasive phenotypes characteristic of transformed cells without activation of Src. Maintaining high levels of CAF1 by exogenous expression suppressed the increased cell motility and invasiveness phenotypes when Src was activated. These data identify a critical role of CAF1 in the dysregulation of cell invasion and motility phenotypes seen in transformed cells and also highlight an important role for epigenetic remodeling through DNA methylation for Src-mediated induction of cancer phenotypes.

Original languageEnglish
Pages (from-to)172-184
Number of pages14
JournalJournal of Biological Chemistry
Volume292
Issue number1
Early online date21 Nov 2016
DOIs
Publication statusPublished - 6 Jan 2017

Keywords

  • DNA-REPLICATION
  • BREAST-CANCER
  • FACTOR-I
  • MESENCHYMAL TRANSITION
  • ONCOGENE
  • LINK
  • FIBROBLASTS
  • INHERITANCE
  • METABOLISM
  • SENESCENCE

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