A dominant SRCAP truncating mutation promotes squamous cell carcinoma progression.

The majority of life-threatening cancers arise from epithelial tissues. These epithelial cancers include cutaneous squamous cell carcinoma (cSCC), the second-most common cancer. cSCC is highly invasive and accounts for an estimated 15,000 deaths each year. We identified SRCAP, a chromatin remodeler that regulates the chromatin occupancy of the histone H2A variant H2A.Z, as a frequently mutated gene in cSCC. Analysis of cSCC mutations in epithelial cancers identified a hotspot truncating mutation in SRCAP, which removes 42% of the protein sequences after amino acid 1879. While SRCAP mutations have been previously connected to the pathogenesis of Floating-Harbor syndrome (FHS), these typically occur downstream, with a hotspot mutation leading to protein truncation after amino acid 2444. We found that expressing the SRCAP-1879 truncation in an HRas-CDK4-driven cSCC model was sufficient to increase proliferation, impair terminal differentiation, and accelerate invasion. Mechanistically, the expression of SRCAP-1879 in primary human keratinocytes was sufficient to dysregulate genes crucial for carcinogenesis (e.g., proliferation, differentiation, and motility) without altering H2A.Z occupancy. In particular, the expression of SRCAP-1879 truncation led to strong induction of the matrix metalloproteinase MMP9 expression level, accompanied by increased keratinocyte cell motility, which was sensitive to matrix metalloprotease inhibition. In contrast, the expression of the SRCAP-FHS truncation did not increase but instead reduced cell motility as well as the expression of MMP9. Taken together, our findings identify a previously under-characterized role of the SRCAP-1879 truncating mutation in promoting multiple aspects of epithelial cancer progression, including invasion, distinct from the well-recognized roles of SRCAP mutations in FHS pathogenesis.