Alternate RASSF1 Transcripts Control SRC Activity, E-Cadherin Contacts, and YAP-Mediated Invasion

Area of Science:

• Oncology
• Molecular Biology
• Epigenetics

Background:

• Tumorigenesis involves SRC kinase activation and loss of cell cohesion.
• The YAP1 cofactor is crucial for RAS-driven tumorigenicity, requiring Hippo pathway inactivation and YES-mediated phosphorylation.
• Mechanisms of SRC kinase activation and Hippo signaling loss in human cancers are unclear.

Purpose of the Study:

• Investigate the role of RASSF1A promoter methylation in YAP1 activation and SRC kinase signaling.
• Elucidate the opposing functions of distinct RASSF1 isoforms in tumor suppression.
• Establish RASSF1 methylation as a biomarker for YAP1 activation and invasive disease.

Main Methods:

• Affinity proteomics
• Proximity ligation assays
• Real-time molecular visualization
• Analysis of RASSF1A promoter methylation in human breast tumors

Main Results:

• RASSF1A promoter methylation reduces YAP phospho-S127, leading to YAP1 derepression.
• RASSF1C isoform promotes SRC/YES kinase activity, targeting SRC/YES to cell junctions and phosphorylating key proteins.
• RASSF1A restricts SRC activity, inhibiting motility, invasion, and tumorigenesis; its epigenetic inactivation correlates with increased pY527-SRC.
• Distinct RASSF1 isoforms exhibit opposing functions, with RASSF1A acting as a tumor suppressor.

Conclusions:

• Epigenetic inactivation of RASSF1A, via promoter methylation, facilitates tumor invasion and progression.
• RASSF1A methylation serves as a biomarker for YAP1 activation and advanced invasive disease.
• Gene transcript switching of RASSF1 isoforms represents an epigenetically controlled tumor suppressor mechanism.