title: FRMD4A upregulation in human squamous cell carcinoma promotes tumor growth and metastasis and is associated with poor prognosis.
abstract: New therapeutic strategies are needed to improve treatment of head and neck squamous cell carcinoma (HNSCC), an aggressive tumor with poor survival rates. FRMD4A is a human epidermal stem cell marker implicated previously in epithelial polarity that is upregulated in SCC cells. Here, we report that FRMD4A upregulation occurs in primary human HNSCCs where high expression levels correlate with increased risks of relapse. FRMD4A silencing decreased growth and metastasis of human SCC xenografts in skin and tongue, reduced SCC proliferation and intercellular adhesion, and stimulated caspase-3 activity and expression of terminal differentiation markers. Notably, FRMD4A attenuation caused nuclear accumulation of YAP, suggesting a potential role for FRMD4A in Hippo signaling. Treatment with the HSP90 inhibitor 17-DMAG or ligation of CD44 with hyaluronan caused nuclear depletion of FRMD4A, nuclear accumulation of YAP and reduced SCC growth and metastasis. Together, our findings suggest FRMD4A as a novel candidate therapeutic target in HNSCC based on the key role in metastatic growth we have identified.
authors.affiliation: CRUK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, United Kingdom.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Goldie
authors.forename: Klaas W
authors.initials: KW
authors.lastname: Mulder
authors.forename: David Wei-Min
authors.initials: DW
authors.lastname: Tan
authors.forename: Scott K
authors.initials: SK
authors.lastname: Lyons
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Sims
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Watt
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D002455:Cell Division; D006801:Humans; D009362:Neoplasm Metastasis; D016133:Polymerase Chain Reaction; D011379:Prognosis; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology; D014062:Tongue Neoplasms / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C574784:FERM domain-containing protein 4A, human; D053148:Caspase 3