RNAi screens identify CHD4 as an essential gene in breast cancer growth

Oncotarget. 2016 Dec 6;7(49):80901-80915. doi: 10.18632/oncotarget.12646.


Epigenetic regulation plays an essential role in tumor development and epigenetic modifiers are considered optimal potential druggable candidates. In order to identify new breast cancer vulnerabilities and improve therapeutic chances for patients, we performed in vivo and in vitro shRNA screens in a human breast cancer cell model (MCF10DCIS.com cell line) using epigenetic libraries. Among the genes identified in our screening, we deeply investigated the role of Chromodomain Helicase DNA binding Protein 4 (CHD4) in breast cancer tumorigenesis. CHD4 silencing significantly reduced tumor growth in vivo and proliferation in vitro of MCF10DCIS.com cells. Similarly, in vivo breast cancer growth was decreased in a spontaneous mouse model of breast carcinoma (MMTV-NeuT system) and in metastatic patient-derived xenograft models. Conversely, no reduction in proliferative ability of non-transformed mammary epithelial cells (MCF10A) was detected. Moreover, we showed that CHD4 depletion arrests proliferation by inducing a G0/G1 block of cell cycle associated with up-regulation of CDKN1A (p21). These results highlight the relevance of genetic screens in the identification of tumor frailties and the role of CHD4 as a potential pharmacological target to inhibit breast cancer growth.

Keywords: CHD4; RNAi screen; breast cancer; epigenetic targets; in vivo murine and human models.

MeSH terms

  • Animals
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Cell Cycle Checkpoints
  • Cell Line, Tumor
  • Cell Proliferation*
  • Computational Biology
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • DNA Helicases / genetics*
  • DNA Helicases / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic
  • Gene Library
  • Gene Regulatory Networks
  • Genetic Predisposition to Disease
  • Humans
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex / genetics*
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex / metabolism
  • Mice, Inbred NOD
  • Mice, SCID
  • Neoplasm Transplantation
  • Phenotype
  • RNA Interference*
  • Signal Transduction
  • Time Factors
  • Tumor Burden


  • CDKN1A protein, human
  • CHD4 protein, human
  • Cdkn1a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p21
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex
  • Mi-2beta protein, mouse
  • DNA Helicases