Glycolytic reprogramming and the EMT drive cervical cancer progression via the NQO1/HIF1α-SIX1 axis
TL;DR
It is demonstrated that NQO1 is significantly upregulated in cervical cancer, promoting proliferation, metastasis, and epithelial-mesenchymal transition (EMT) and is a promising therapeutic target.
Abstract
Summary Cervical cancer aggressiveness and therapeutic resistance are driven by metabolic reprogramming and redox imbalance. Within this context, NAD(P)H: quinone oxidoreductase 1 (NQO1), a critical regulator of cellular redox homeostasis and energy metabolism, is highly expressed in several types of cancer and is associated with poor prognosis; however, its role in cervical cancer remains unclear. This study demonstrates that NQO1 is significantly upregulated in cervical cancer, promoting proliferation, metastasis, and epithelial-mesenchymal transition (EMT). Mechanistically, NQO1 suppresses AMP-activated protein kinase (AMPK) phosphorylation to reduce reactive oxygen species (ROS), while stabilizing HIF1α by preventing its proteasomal degradation. Consequently, stabilized HIF1α upregulates sine oculis homeobox 1 (SIX1) to enhance glycolytic enzyme transcription, driving aerobic glycolysis. Functional rescue experiments demonstrated that knockdown of NQO1, HIF1α, or SIX1 significantly inhibited glycolytic flux, tumor growth, and metastasis in vivo. Thus, the NQO1/HIF1α-SIX1 axis orchestrates metabolic reprogramming and EMT to promote cervical cancer progression and is a promising therapeutic target.