CDCA8 promotes bladder cancer survival by stabilizing HIF1α expression under hypoxia

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Hypoxia is a key characteristic of solid tumors, driving tumor cell adaptation and survival.
• Hypoxia-inducible factor 1-alpha (HIF1α) is a critical regulator of cellular responses to low oxygen environments.
• Bladder cancer (BCa) progression is often associated with hypoxic conditions.

Purpose of the Study:

• To investigate the role of cell cycle division-related gene 8 (CDCA8) in bladder cancer cells under hypoxic conditions.
• To elucidate the molecular mechanisms by which CDCA8 influences BCa cell survival in hypoxia.
• To evaluate CDCA8 as a potential therapeutic target in bladder cancer.

Main Methods:

• Analysis of CDCA8 expression in BCa cell lines and clinical samples.
• Assessment of CDCA8's requirement for BCa cell survival under hypoxia.
• Investigation of the interaction between CDCA8, HIF1α, PTEN, and AKT signaling.
• Luciferase reporter assays to confirm HIF1α-mediated transcriptional activation of CDCA8.

Main Results:

• CDCA8 was significantly upregulated in BCa cell lines and clinical samples, correlating with advanced stage, grade, and poor overall survival (OS).
• CDCA8 protein expression was essential for BCa cell survival in hypoxic environments.
• CDCA8 stabilizes HIF1α by competing with PTEN for AKT binding, leading to PTEN displacement and activation of the AKT/GSK3β pathway.
• HIF1α directly binds to the CDCA8 promoter, creating a positive-feedback loop that enhances HIF1α stability.

Conclusions:

• CDCA8 plays a crucial role in enabling bladder cancer cells to adapt to and survive oxygen deprivation.
• The CDCA8-HIF1α positive-feedback loop is vital for sustaining bladder cancer cells in a hypoxic tumor microenvironment.
• CDCA8 represents a novel and promising therapeutic target for bladder cancer treatment.