Targeting of the tumor suppressor GRHL3 by a miR-21-dependent proto-oncogenic network results in PTEN loss and tumorigenesis

Cancer Cell. 2011 Nov 15;20(5):635-48. doi: 10.1016/j.ccr.2011.10.014.

Abstract

Despite its prevalence, the molecular basis of squamous cell carcinoma (SCC) remains poorly understood. Here, we identify the developmental transcription factor Grhl3 as a potent tumor suppressor of SCC in mice, and demonstrate that targeting of Grhl3 by a miR-21-dependent proto-oncogenic network underpins SCC in humans. Deletion of Grhl3 in adult epidermis evokes loss of expression of PTEN, a direct GRHL3 target, resulting in aggressive SCC induced by activation of PI3K/AKT/mTOR signaling. Restoration of Pten expression completely abrogates SCC formation. Reduced levels of GRHL3 and PTEN are evident in human skin, and head and neck SCC, associated with increased expression of miR-21, which targets both tumor suppressors. Our data define the GRHL3-PTEN axis as a critical tumor suppressor pathway in SCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Carcinoma, Squamous Cell / chemically induced
  • Carcinoma, Squamous Cell / genetics*
  • Cell Differentiation / genetics
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Gene Deletion
  • Gene Expression Regulation, Neoplastic
  • Genetic Predisposition to Disease
  • Homeostasis
  • Keratinocytes / pathology
  • Mice
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • MicroRNAs / physiology*
  • Molecular Sequence Data
  • PTEN Phosphohydrolase / genetics*
  • Sequence Alignment
  • Skin Neoplasms / chemically induced
  • Skin Neoplasms / genetics*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism
  • Tumor Suppressor Proteins / physiology*

Substances

  • DNA-Binding Proteins
  • Grhl3 protein, mouse
  • MIRN21 microRNA, mouse
  • MicroRNAs
  • Transcription Factors
  • Tumor Suppressor Proteins
  • PTEN Phosphohydrolase
  • Pten protein, mouse

Associated data

  • GENBANK/GSE32868