HOXA9 inhibits HIF-1α-mediated glycolysis through interacting with CRIP2 to repress cutaneous squamous cell carcinoma...

Area of Science:

• Oncology
• Molecular Biology
• Cancer Metabolism

Background:

• Glycolytic reprogramming is common in cancers, but its regulators in cutaneous squamous cell carcinoma (cSCC) are not well understood.
• Homeobox A9 (HOXA9), a target of onco-miR-365, is found to be downregulated in cSCC.

Purpose of the Study:

• To investigate the role of HOXA9 in regulating glucose metabolism in cSCC.
• To elucidate the molecular mechanisms by which HOXA9 affects glycolysis and HIF-1α signaling in cSCC.

Main Methods:

• Quantitative analysis of HOXA9 expression in cSCC tumors and cell lines.
• In vitro and in vivo studies to assess HOXA9's effect on glycolysis.
• Mechanistic investigations involving HIF-1α, HK2, GLUT1, PDK1, and CRIP2 interactions.

Main Results:

• HOXA9 is significantly downregulated in cSCC and acts as a tumor suppressor.
• HOXA9 inhibits glycolysis by negatively regulating HIF-1α and its downstream targets (HK2, GLUT1, PDK1).
• HOXA9-CRIP2 interaction at gene promoters hinders HIF-1α binding, thereby repressing glycolytic gene expression.

Conclusions:

• A miR-365-HOXA9-HIF-1α regulatory axis promotes enhanced glycolysis in cSCC development.
• HOXA9's tumor-suppressive function and regulation of glycolysis present a potential therapeutic target for cSCC.