AMPK-activated BAP1 regulates pVHL stability and tumor-suppressive functions

Area of Science:

• Oncology
• Molecular Biology
• Cancer Metabolism

Background:

• The von Hippel-Lindau (VHL) protein (pVHL) is a tumor suppressor frequently downregulated in cancers with wild-type VHL, but the mechanisms are unclear.
• Aberrant glucose metabolism is a cancer hallmark, yet its link to pVHL stability and function is undefined.

Purpose of the Study:

• To investigate the connection between glucose homeostasis and pVHL turnover.
• To elucidate the mechanism by which dysregulated glucose metabolism impacts pVHL function in cancer.

Main Methods:

• Investigated pVHL destabilization under glucose starvation, 2-deoxyglucose (2-DG), and metformin in cancer cells.
• Utilized in vitro and in vivo models, including patient-derived xenografts.
• Analyzed correlations between phosphorylated AMPKα, BAP1, and pVHL levels in clinical cancer specimens.

Main Results:

• Dysregulated glucose metabolism destabilizes pVHL in pancreatic ductal adenocarcinoma, colorectal, and ovarian cancer cells.
• Energy stress activates AMP-activated protein kinase (AMPK), which phosphorylates BAP1, enhancing its interaction with and stabilization of pVHL.
• Disrupting BAP1 phosphorylation impairs pVHL stabilization and accelerates tumor progression; clinical data show positive correlations between p-AMPKα, pSer123-BAP1, and pVHL.

Conclusions:

• A novel mechanism links aberrant glucose metabolism to the compromised BAP1-pVHL tumor-suppressive axis.
• Therapeutic strategies targeting this pathway may offer new treatments for cancers with downregulated VHL and altered glucose metabolism.