Kruppel-family zinc finger proteins as emerging epigenetic biomarkers in head and neck squamous cell carcinoma

Patrick Pearson, Kendra Smith, Nilita Sood, Elizabeth Chia, Alicia Follett, Michael B. Prystowsky, Simon Kirby, Thomas J. Belbin

Krüppel-type zinc finger protein genes located on chromosome 19q13 are aberrantly hypermethylated with high frequency in all anatomic sub-sites of head and neck cancers as well as other epithelial tumours resulting in decreased expression. We examined prognostic significance of ZNF154 and ZNF132 expression and DNA methylation in independent patient cohort of about 500 head and neck cancer patients in the Cancer Genome Atlas (TCGA). We also overexpressed these genes in HEK-293 cells, as well as the oral cancer cell line UM-SCC-1. In 20 patients from the TCGA cohort of HNSCC patients where ZNF154 and ZNF132 DNA methylation and RNA expression could be compared in tumor and adjacent normal tissue, there was increased DNA methylation and decreased expression of both ZNF154 and ZNF132 in primary tumours. Low ZNF154 and low ZNF132 expression were associated with shorter overall survival in both head and neck squamous cell carcinoma (HNSCC) and lung adenocarcinoma (LUAC patients). While expression of these proteins in HEK-293 cells produced full-length protein, only truncated copies could be expressed in head and neck cancer cells (UM-SCC-1). The truncated version of ZNF154 protein increased doubling time and reduced cell migration in UM-SCC-1 cancer cells. Both ZNF132 and ZNF154 represent novel clinically significant biomarkers in head and neck cancer with potential tumour suppressive properties. Future studies will address the underlying molecular mechanisms by which ZNF154 expression in HNSCC contributes to the control of cell growth and migration.