Dampened Regulatory Circuitry of TEAD1/ITGA1/ITGA2 Promotes TGFβ1 Signaling to Orchestrate Prostate Cancer...

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Extracellular matrix (ECM) alterations are crucial in prostate cancer (PCa) progression, influencing tumor growth and invasion.
• Integrins, specifically ITGA1 and ITGA2, play a role in PCa, but their precise function in progression requires further elucidation.

Approach:

• Conducted a meta-analysis of multiple PCa cohorts to identify associations between integrin gene expression and tumor progression.
• Utilized genome-wide co-expression analysis to identify key regulators of ITGA1 and ITGA2 expression in PCa.
• Investigated the mechanistic link between integrin loss, epithelial-to-mesenchymal transition (EMT), and PCa aggressiveness.

Key Points:

• Downregulation or genomic loss of ITGA1 and ITGA2 integrin genes correlates with advanced PCa and worse patient prognosis.
• Loss of ITGA1/ITGA2 activates TGFβ1 signaling and YAP1 nuclear translocation, inducing EMT and enhancing prostate cancer cell invasion.
• The transcription factor TEAD1 is identified as a critical regulator of ITGA1 and ITGA2 expression in PCa.

Conclusions:

• Loss of α1- and α2-integrins, through ITGA1/ITGA2 locus deletion or TEAD1 inactivation, drives PCa progression.
• TEAD1 downregulation or loss synergizes with low ITGA1/ITGA2 expression to worsen PCa prognosis and progression.
• Targeting the TEAD1-integrin axis or TGFβ1-driven EMT may offer therapeutic strategies for aggressive prostate cancer.