Cancer cell adaptation to hypoxia involves a HIF-GPRC5A-YAP axis

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• Hypoxia, or low oxygen, is characteristic of solid tumors and essential for cancer cell survival.
• Identifying molecular targets that hypoxic cancer cells rely on is a significant challenge in cancer research.

Purpose of the Study:

• To identify novel hypoxia-induced proteins crucial for cancer cell survival.
• To elucidate the molecular mechanisms by which these proteins promote cancer cell adaptation to hypoxia.

Main Methods:

• Utilized SILAC-based proteomics to discover hypoxia-induced proteins.
• Employed genetic approaches in vitro and in vivo to study gene regulation and function.
• Analyzed patient data for correlations between gene expression, clinical outcomes, and hypoxia signatures.

Main Results:

• Identified G protein-coupled receptor GPRC5A as a novel hypoxia-induced protein that protects cancer cells from apoptosis.
• Demonstrated that Hypoxia-Inducible Factors (HIFs) directly activate GPRC5A transcription.
• Found GPRC5A upregulation in mesenteric ischemia and its correlation with poor outcomes in colorectal cancers.
• Showed GPRC5A promotes hypoxic cell survival by activating the Hippo pathway effector YAP and its target BCL2L1.
• Confirmed that constitutively active YAP can rescue apoptosis induced by GPRC5A depletion in hypoxia.

Conclusions:

• Identified a novel HIF-GPRC5A-YAP signaling axis critical for the adaptive response to hypoxia in cancer.
• GPRC5A plays a key role in mediating cancer cell survival under hypoxic conditions.
• The HIF-GPRC5A-YAP axis represents a potential therapeutic target for treating hypoxic tumors.