YAP induces malignant mesothelioma cell proliferation by upregulating transcription of cell cycle-promoting genes

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• Malignant mesothelioma (MM) frequently involves neurofibromatosis type 2 (NF2) gene inactivation.
• The Hippo signaling pathway, regulated by Merlin (NF2 product), controls organ size and is implicated in cancer.
• Overexpression of Yes-associated protein (YAP), a key Hippo pathway effector, is observed in MM, often due to NF2, LATS2, or SAV1 gene alterations, or YAP amplification.

Purpose of the Study:

• To elucidate the specific roles of YAP in malignant mesothelioma.
• To identify YAP target genes that promote MM cell growth and survival.
• To understand the mechanisms by which YAP contributes to MM aggressiveness.

Main Methods:

• YAP knockdown was performed in MM cells to assess effects on cell behavior.
• Gene expression analysis was conducted in MM cell lines with constitutive YAP activation.
• Direct transcriptional targets of YAP were identified using techniques including TEAD transcription factor co-activity assessment.
• Knockdown of identified target genes (CCND1, FOXM1) was performed to evaluate their impact on MM cell proliferation.

Main Results:

• YAP knockdown significantly inhibited MM cell motility, invasion, anchorage-independent growth, and proliferation in vitro.
• Commonly regulated genes by YAP in MM cells primarily included cell cycle regulators.
• YAP was found to directly induce CCND1 and FOXM1 transcription via cooperation with TEAD.
• Knockdown of CCND1 and FOXM1 partially suppressed MM cell proliferation, with less potent effects than YAP knockdown.

Conclusions:

• Constitutive YAP activation in malignant mesothelioma cells drives aggressive phenotypes.
• YAP promotes MM cell cycle progression, contributing to increased proliferation, motility, and invasion.
• YAP-induced CCND1 and FOXM1 are key mediators of YAP's pro-proliferative effects in MM.