Oral Presentation 2014 Cutaneous Biology Meeting

Identification of a novel proto-oncogenic network in head and neck squamous cell carcinoma in mice and humans (#1)

Smitha R. Georgy 1 , Michael Cangkrama 1 , Seema Srivastava 1 , Darren Partridge 1 , Alana Auden 1 , Sebastian Dworkin 1 , Catriona A. McLean 2 , Stephen Jane 1 3 , Charbel Darido 1
  1. Department of Medicine, Monash University Central Clinical School, Prahran, Vic, Australia
  2. Department of Anatomical Pathology, Alfred Hospital, Prahran, Victoria, Australia
  3. Department of Hematology, Alfred Hospital, Prahran, Victoria, Australia

Epidermal deletion of GRHL3 induces skin squamous cell carcinoma (SCC) through PTEN loss and PI3K/AKT/mTOR activation. Here, we demonstrate that GRHL3 also exhibits potent tumor suppressor activity for head and neck SCC (HNSCC) via an alternate novel proto-oncogenic network. Deletion of GRHL3 in oral epithelium evokes loss of GSK3B expression resulting in stabilisation and accumulation of c-MYC, and aggressive SCC. This molecular signature is evident in a subset of human HNSCC. Loss of Gsk3b, independent of Grhl3, induces HNSCC in vivo, and restoration of GSK3B expression blocks proliferation of human HNSCC cells in vitro. Target gene specificity in oral epithelium versus epidermis determines which proto-oncogenic pathway is activated in GRHL3-deficient SCCs, paving the way for more directed therapies in these cancers.