Androgen Receptor Regulates CD44 Expression in Bladder Cancer

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Androgen receptor (AR) plays a role in bladder cancer development.
• Reduced AR expression is linked to advanced bladder cancer stage and grade.
• Mechanisms underlying the AR-bladder cancer progression relationship require elucidation.

Purpose of the Study:

• To investigate the functional genomics of AR signaling in bladder cancer.
• To identify genes regulated by androgen stimulation in bladder cancer cells.
• To explore the relationship between AR and CD44 in bladder cancer progression.

Main Methods:

• Chromatin immunoprecipitation sequencing and transcriptomic analysis of AR-expressing bladder cancer cells.
• In vitro stimulation with synthetic androgen R1881.
• In vivo functional genomics using pooled shRNA and open reading frame libraries.
• CRISPR-based mutagenesis to identify regulatory elements.

Main Results:

• Androgen stimulation identified CD44, a hyaluronic acid receptor and cancer driver, as significantly associated.
• A novel silencer element regulating CD44 expression was identified via CRISPR mutagenesis.
• Tumor AR and CD44 mRNA and protein expression were inversely correlated in human bladder cancer patients.

Conclusions:

• A novel mechanism explaining the inverse relationship between AR and bladder cancer progression is described.
• The identified AR-CD44 axis suggests potential utility for prognostication and therapeutic selection.
• Novel androgen response elements (AREs) that suppress CD44 were discovered.