ATAD3A promotes bladder cancer progression by regulating glycolysis through MYC stabilization

Area of Science:

• Oncology
• Molecular Biology
• Cancer Metabolism

Background:

• Bladder cancer (BCa) presents significant challenges due to high recurrence and progression rates.
• Metabolic reprogramming, particularly glycolysis, is crucial in cancer, but its drivers in BCa are not fully understood.
• The role of mitochondrial protein ATAD3A in BCa progression and metabolism has not been previously investigated.

Purpose of the Study:

• To investigate the role of ATAD3A in bladder cancer progression.
• To elucidate the molecular mechanisms by which ATAD3A influences tumor metabolism.
• To explore the link between ATAD3A, MYC stability, and glycolysis in BCa.

Main Methods:

• Analysis of TCGA-BLCA data for ATAD3A expression and clinical correlation.
• In vitro functional assays (proliferation, migration, invasion, metabolic flux analysis) in BCa cell lines with altered ATAD3A levels.
• In vivo studies using subcutaneous xenograft models.
• Quantitative proteomics and mechanistic studies (ubiquitination, protein stability assays) to identify downstream targets and regulatory pathways.

Main Results:

• ATAD3A is upregulated in BCa and correlates with advanced stage and poor prognosis.
• ATAD3A knockdown inhibits BCa cell proliferation, migration, invasion, and tumor growth, while overexpression enhances these phenotypes.
• ATAD3A promotes glycolysis by stabilizing MYC protein via the USP10 deubiquitinase, thereby increasing glucose uptake and lactate production.
• Inhibition of glycolysis or restoration of MYC/USP10 function reverses the effects of ATAD3A modulation.

Conclusions:

• ATAD3A drives bladder cancer progression through the ATAD3A-USP10-MYC axis, which enhances glycolytic reprogramming.
• This pathway represents a promising therapeutic target for bladder cancer treatment.