Overexpression of YAP1 induces immortalization of normal human keratinocytes by blocking clonal evolution

Area of Science:

• Cell Biology
• Molecular Biology
• Oncology

Background:

• The role of YAP1 (Yes-associated protein 1) in cancer is complex, with evidence suggesting both oncogenic and tumor-suppressive functions.
• YAP1's function in rapidly renewing tissues like skin keratinocytes remains incompletely understood.
• Investigating YAP1's role is crucial for understanding cell physiology and potential therapeutic targets.

Purpose of the Study:

• To elucidate the function of YAP1 in primary human keratinocytes.
• To determine if YAP1 overexpression induces immortalization or malignant transformation in these cells.
• To analyze the impact of YAP1 on keratinocyte proliferation, differentiation, and epithelial-mesenchymal transition (EMT).

Main Methods:

• Overexpression of YAP1 in primary human keratinocytes.
• Assessment of cell proliferation, colony-forming efficiency, and holoclone formation.
• Analysis of senescence escape, soft agar growth, and mesenchymal marker expression.
• Evaluation of epithelial proliferation and differentiation markers, including LEKTI.

Main Results:

• YAP1 overexpression blocked clonal evolution and induced immortalization in keratinocytes.
• Increased cell proliferation, colony-forming efficiency, and holoclone percentage were observed.
• Cells escaped senescence and became immortalized but did not undergo malignant transformation or EMT.
• Epithelial proliferation markers increased, while differentiation markers, including LEKTI, decreased significantly.

Conclusions:

• YAP1 overexpression in keratinocytes promotes cell immortalization and sustained proliferation without inducing tumorigenesis.
• YAP1 appears to maintain keratinocytes in a proliferative state, preventing differentiation.
• These findings suggest YAP1's role in regulating the balance between proliferation and differentiation in epithelial tissues.