A dominant SRCAP truncating mutation promotes squamous cell carcinoma progression.

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Epithelial cancers, including cutaneous squamous cell carcinoma (cSCC), are a major cause of cancer deaths.
• The SRCAP gene, a chromatin remodeler, is frequently mutated in cSCC.
• SRCAP mutations are known to cause Floating-Harbor syndrome (FHS), but their role in cSCC is less understood.

Purpose of the Study:

• To investigate the role of a specific SRCAP truncating mutation (SRCAP-1879) in cSCC pathogenesis.
• To differentiate the effects of the SRCAP-1879 mutation from SRCAP mutations associated with FHS.

Main Methods:

• Analysis of cSCC mutations to identify a hotspot SRCAP truncation (SRCAP-1879).
• Expression of SRCAP-1879 and SRCAP-FHS truncations in a cSCC model and primary human keratinocytes.
• Assessment of proliferation, differentiation, invasion, gene expression (MMP9), and cell motility.

Main Results:

• The SRCAP-1879 mutation significantly increased proliferation, impaired differentiation, and accelerated invasion in cSCC models.
• SRCAP-1879 dysregulated key cancer-related genes in keratinocytes without altering H2A.Z occupancy.
• SRCAP-1879 strongly induced MMP9 expression and keratinocyte motility, unlike the SRCAP-FHS mutation which reduced motility.

Conclusions:

• The SRCAP-1879 truncating mutation plays a distinct and significant role in promoting epithelial cancer progression, particularly invasion.
• This finding expands the understanding of SRCAP's function in cancer beyond its known role in FHS.
• Targeting MMP9 may offer therapeutic strategies for cSCC driven by SRCAP-1879 mutations.